ClinVar Genomic variation as it relates to human health
NM_003784.4(SERPINB7):c.796C>T (p.Arg266Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003784.4(SERPINB7):c.796C>T (p.Arg266Ter)
Variation ID: 102446 Accession: VCV000102446.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.33 18: 63804288 (GRCh38) [ NCBI UCSC ] 18: 61471522 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 10, 2014 May 12, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003784.4:c.796C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003775.1:p.Arg266Ter nonsense NM_001040147.3:c.796C>T NP_001035237.1:p.Arg266Ter nonsense NM_001261830.2:c.796C>T NP_001248759.1:p.Arg266Ter nonsense NM_001261831.2:c.745C>T NP_001248760.1:p.Arg249Ter nonsense NC_000018.10:g.63804288C>T NC_000018.9:g.61471522C>T NG_034150.1:g.56242C>T - Protein change
- R266*, R249*
- Other names
- SERPINB7, ARG266TER (rs142859678)
- Canonical SPDI
- NC_000018.10:63804287:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00240 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00043
Exome Aggregation Consortium (ExAC) 0.00054
The Genome Aggregation Database (gnomAD), exomes 0.00055
1000 Genomes Project 30x 0.00203
1000 Genomes Project 0.00240
The Genome Aggregation Database (gnomAD) 0.00019
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SERPINB7 | - | - |
GRCh38 GRCh37 |
66 | 158 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000088682.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000479535.23 | |
SERPINB7-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2023 | RCV003415873.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000567359.9
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost, and other loss-of-function variants have been reported in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 24514002, 27786350, 27663160, 27569382, 27543371, 27506501, 28211129, 29888704, 30256384, 30581033, 30833958, 30004585, 32406097, 31980526, 24077912, 34426522, 33362511, 32892407, 33914963, 34379845, 27666198, 24207119, 24773080) (less)
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Pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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SERPINB7-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108780.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SERPINB7 c.796C>T variant is predicted to result in premature protein termination (p.Arg266*). This variant has been reported to be causative for autosomal recessive Nagashima-type … (more)
The SERPINB7 c.796C>T variant is predicted to result in premature protein termination (p.Arg266*). This variant has been reported to be causative for autosomal recessive Nagashima-type palmoplantar keratosis and has been described as a founder mutation in Asian populations (Kubo et al. 2013. PubMed ID: 24207119; Yin et al. 2014. PubMed ID: 24514002; Zhang et al. 2016. PubMed ID: 27666198). This variant is reported in 0.69% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-61471522-C-T). Nonsense variants in SERPINB7 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Palmoplantar keratoderma, Nagashima type
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894164.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Palmoplantar keratoderma, Nagashima type
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058138.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000102446, PMID:24207119, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000527, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Palmoplantar keratosis (present) , Thickened skin (present)
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Pathogenic
(Dec 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Palmoplantar keratoderma, Nagashima type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761696.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Mar 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Palmoplantar keratoderma, Nagashima type
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020073.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003283223.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg266*) in the SERPINB7 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg266*) in the SERPINB7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the SERPINB7 protein. This variant is present in population databases (rs142859678, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Nagashima-type palmoplantar keratoderma (NPPK) (PMID: 24207119, 24514002, 27543371, 27666198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Japanese and Han Chinese ancestry (PMID: 24514002, 24773080). ClinVar contains an entry for this variant (Variation ID: 102446). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Palmoplantar keratoderma, Nagashima type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812579.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in SERPINB7 is a nonsense variant predicted to cause a premature stop codon, p.(Arg266*), that is predicted to escape nonsense-mediated decay and … (more)
This sequence change in SERPINB7 is a nonsense variant predicted to cause a premature stop codon, p.(Arg266*), that is predicted to escape nonsense-mediated decay and remove <10% of the protein (removes amino acids 226-380) in a gene where loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.8% (347/44,860 alleles) in the East Asian population, which is higher than expected for a recessive disease. However, this variant is an East Asian founder mutation for Nagashima-type palmoplantar keratoderma. It has been reported in multiple affected individuals in the homozygous and compound heterozygous state (with at least one individual with a pathogenic variant on the second allele) and segregates with disease in at least one family (PMID: 24207119, 35178744). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PVS1_Strong, PP1, BS1. (less)
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Pathogenic
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247832.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 01, 2014)
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no assertion criteria provided
Method: literature only
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PALMOPLANTAR KERATODERMA, NAGASHIMA TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000121604.2
First in ClinVar: Mar 20, 2014 Last updated: Nov 10, 2014 |
Comment on evidence:
In 6 unrelated Japanese patients with the Nagashima type of palmoplantar keratoderma (PPKN; 615598), Kubo et al. (2013) identified homozygosity for a c.796C-T transition in … (more)
In 6 unrelated Japanese patients with the Nagashima type of palmoplantar keratoderma (PPKN; 615598), Kubo et al. (2013) identified homozygosity for a c.796C-T transition in exon 8 of the SERPINB7 gene, resulting in an arg266-to-ter (R266X) substitution. Seven more unrelated Japanese PPKN patients were compound heterozygous for R266X and another truncating mutation in SERPINB7: the second mutation in 5 of the patients was a 2-bp deletion/12-bp insertion (c.218_219delAGinsTAAACTTTACCT; 603357.0002) at the end of exon 3, causing a frameshift predicted to result in a premature stop codon (Gln73LeufsTer17); the second mutation in the remaining 2 patients was a splice site mutation (c.455-1G-A; 603357.0003) in intron 5, also predicted to result in a premature stop codon (Gly152ValfsTer21). In the 9 sets of unaffected parents available for study, each was heterozygous for 1 of the mutations. The R266X variant was identified as a SNP (rs142859678) in the 1000 Genomes Project database with a minor allele frequency of 0.4%. R266X was present in heterozygosity in 2 of 89 Japanese individuals, 4 of 97 Han Chinese individuals from Beijing, and 2 of 100 Han Chinese individuals from southern China, but was not found in any of 806 non-Asian individuals, suggesting that R266X is a founder mutation causing PPKN in Asian populations. In 4 unrelated Chinese patients with PPKN, Yin et al. (2014) identified homozygosity for the R266X mutation in the SERPINB7 gene; R266X was present in compound heterozygosity with another truncating mutation in 2 additional PPKN patients. All 10 available parents were unaffected heterozygous carriers of the respective mutations. SNP analysis suggested that the 6 patients shared a common mutant haplotype, indicating that R266X likely represents a founder mutation rather than a mutation hotspot. In 4 Japanese families with PPKN, including 1 with a pseudodominant pattern of inheritance, Mizuno et al. (2014) identified homozygosity for the R266X mutation. In 6 additional families, affected individuals were compound heterozygous for R266X and another mutation in the SERPINB7 gene: in 3 families, the second mutation was the previously identified 2-bp deletion/12-bp insertion (603357.0002), whereas in another 2 families, the second allele carried the previously identified splice site mutation in IVS5 (603357.0003). In 1 family, the second mutation was a different splice site mutation, c.336+3T-G, which was not found in 50 ethnically matched controls. (less)
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Palmoplantar keratoderma, nagashima type
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142482.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_003784.3:c.796C>T in the SERPINB7 gene has an allele frequency of 0.007 Asia in East Asian subpopulation in the gnomAD database. This variant is predicted to … (more)
NM_003784.3:c.796C>T in the SERPINB7 gene has an allele frequency of 0.007 Asia in East Asian subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Palmoplantar keratoderma, nagashima type, compound heterozygous with c.218_219del2ins12, c.455-1G>A, respectively (PMID: 24207119). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3_Strong; PP4. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Two novel mutations of SERPINB7 in eight cases of Nagashima-type palmoplantar keratosis in the Chinese population. | Xiao T | The Journal of dermatology | 2022 | PMID: 35178744 |
Identification of SERPINB7 mutations in Korean patients with Nagashima-type palmoplantar keratosis. | On HR | The Journal of dermatology | 2017 | PMID: 27543371 |
Nagashima-type palmoplantar keratosis in a Chinese Han population. | Zhang J | Molecular medicine reports | 2016 | PMID: 27666198 |
Highly prevalent SERPINB7 founder mutation causes pseudodominant inheritance pattern in Nagashima-type palmoplantar keratosis. | Mizuno O | The British journal of dermatology | 2014 | PMID: 24773080 |
New and recurrent SERPINB7 mutations in seven Chinese patients with Nagashima-type palmoplantar keratosis. | Yin J | The Journal of investigative dermatology | 2014 | PMID: 24514002 |
Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis. | Kubo A | American journal of human genetics | 2013 | PMID: 24207119 |
Text-mined citations for rs142859678 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.