ClinVar Genomic variation as it relates to human health
NM_006907.4(PYCR1):c.355C>T (p.Arg119Cys)
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_006907.4(PYCR1):c.355C>T (p.Arg119Cys)
Variation ID: 488456 Accession: VCV000488456.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 81935111 (GRCh38) [ NCBI UCSC ] 17: 79892987 (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 Feb 8, 2018 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006907.4:c.355C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008838.2:p.Arg119Cys missense NM_001282279.2:c.355C>T NP_001269208.1:p.Arg119Cys missense NM_001282280.2:c.355C>T NP_001269209.1:p.Arg119Cys missense NM_001282281.2:c.436C>T NP_001269210.1:p.Arg146Cys missense NM_001330523.2:c.355C>T NP_001317452.1:p.Arg119Cys missense NM_153824.3:c.355C>T NP_722546.1:p.Arg119Cys missense NC_000017.11:g.81935111G>A NC_000017.10:g.79892987G>A NG_023032.1:g.6982C>T - Protein change
- R119C, R146C
- Other names
- -
- Canonical SPDI
- NC_000017.11:81935110:G:A
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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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00014
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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PYCR1 | - | - |
GRCh38 GRCh37 |
292 | 319 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (2) |
criteria provided, single submitter
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Oct 30, 2019 | RCV000578310.2 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV001550766.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2022 | RCV002509452.1 | |
PYCR1-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 29, 2023 | RCV003945359.1 |
Pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2024 | RCV003992334.1 |
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
(Oct 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive cutis laxa type 2B
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001525291.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Oct 06, 2023)
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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: SCV001771152.2
First in ClinVar: Aug 07, 2021 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: decreased protein levels observed in transfected cells, compared to wild type, suggesting the variant is associated with protein … (more)
Published functional studies demonstrate a damaging effect: decreased protein levels observed in transfected cells, compared to wild type, suggesting the variant is associated with protein instability (Nakayama et al., 2015); This variant is associated with the following publications: (PMID: 30450527, 23963297, 28294978, Tramontana 2021[Case report], 35599849, 24035636, 25865492, 33771508) (less)
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Pathogenic
(Dec 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cutis laxa
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819362.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: PYCR1 c.355C>T (p.Arg119Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: PYCR1 c.355C>T (p.Arg119Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 246662 control chromosomes. c.355C>T has been reported in the literature in multiple individuals affected with Cutis Laxa - PYCR1 Related phenotypes (Example: Dimopoulou_2013, Gardeitchik_2014, Lessel_2018 and Nakayama_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating less than 2% cell activity compared to Wildtype in lymphoblastoid cell lines (Nakayama_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 27, 2023)
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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: SCV002244565.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 119 of the PYCR1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 119 of the PYCR1 protein (p.Arg119Cys). This variant is present in population databases (rs121918376, gnomAD 0.08%). This missense change has been observed in individuals with cutis laxa (PMID: 23963297, 24035636, 30450527). ClinVar contains an entry for this variant (Variation ID: 488456). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PYCR1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PYCR1 function (PMID: 25865492). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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PYCR1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004757029.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The PYCR1 c.355C>T variant is predicted to result in the amino acid substitution p.Arg119Cys. This variant was reported in individuals presenting with autosomal recessive cutis … (more)
The PYCR1 c.355C>T variant is predicted to result in the amino acid substitution p.Arg119Cys. This variant was reported in individuals presenting with autosomal recessive cutis laxa (Table 2, Dimopoulou et al. 2013. PubMed ID: 24035636; Table 2, Gardeitchik et al. 2013. PubMed ID: 23963297). It has also been reported in the homozygous state in individuals with microcephaly, hypomyelination, hypotonia, and developmental and white matter anomalies (Nakayama et al. 2015. PubMed ID: 25865492; Individual 6, Lessel et al. 2018. PubMed ID: 30450527). This variant is reported in 0.049% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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PYCR1-related de Barsy syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809523.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Jul 28, 2017)
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no assertion criteria provided
Method: clinical testing
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PYCR1-related cutis laxa
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000680123.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800370.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808357.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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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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Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. | Lessel D | Human genetics | 2018 | PMID: 30450527 |
Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. | Nakayama T | American journal of human genetics | 2015 | PMID: 25865492 |
Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa. | Gardeitchik T | European journal of human genetics : EJHG | 2014 | PMID: 23963297 |
Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. | Dimopoulou A | Molecular genetics and metabolism | 2013 | PMID: 24035636 |
Text-mined citations for rs121918376 ...
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.