NM_005271.5(GLUD1):c.1498G>A (p.Ala500Thr) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003479053.1

Allele description [Variation Report for NM_005271.5(GLUD1):c.1498G>A (p.Ala500Thr)]

NM_005271.5(GLUD1):c.1498G>A (p.Ala500Thr)

Gene:

GLUD1:glutamate dehydrogenase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.2

Genomic location:

Preferred name:

NM_005271.5(GLUD1):c.1498G>A (p.Ala500Thr)

HGVS:

NC_000010.11:g.87053401C>T
NG_013010.1:g.46619G>A
NM_001318900.1:c.1099G>A
NM_001318901.1:c.997G>A
NM_001318902.1:c.997G>A
NM_001318904.2:c.997G>A
NM_001318905.2:c.997G>A
NM_001318906.2:c.997G>A
NM_005271.5:c.1498G>AMANE SELECT
NP_001305829.1:p.Ala367Thr
NP_001305830.1:p.Ala333Thr
NP_001305831.1:p.Ala333Thr
NP_001305833.1:p.Ala333Thr
NP_001305834.1:p.Ala333Thr
NP_001305835.1:p.Ala333Thr
NP_005262.1:p.Ala500Thr
NC_000010.10:g.88813158C>T
NM_005271.3:c.1498G>A

Protein change:

A333T

Links:

dbSNP: rs797045597

NCBI 1000 Genomes Browser:

rs797045597

Molecular consequence:

NM_001318900.1:c.1099G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318901.1:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318902.1:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318904.2:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318905.2:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318906.2:c.997G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005271.5:c.1498G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004223543	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10871207, 23506826, 36239000 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004223543

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 8, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators.

Stanley CA, Fang J, Kutyna K, Hsu BY, Ming JE, Glaser B, Poncz M.

Diabetes. 2000 Apr;49(4):667-73.

PubMed [citation]

PMID:: 10871207

Congenital hyperinsulinism: clinical and molecular analysis of a large Italian cohort.

Faletra F, Athanasakis E, Morgan A, Biarnés X, Fornasier F, Parini R, Furlan F, Boiani A, Maiorana A, Dionisi-Vici C, Giordano L, Burlina A, Ventura A, Gasparini P.

Gene. 2013 May 25;521(1):160-5. doi: 10.1016/j.gene.2013.03.021. Epub 2013 Mar 16.

PubMed [citation]

PMID:: 23506826

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004223543.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: GLUD1 c.1498G>A (p.Ala500Thr) results in a non-conservative amino acid change located in the Glutamate/phenylalanine/leucine/valine/L-tryptophan dehydrogenase, C-terminal domain (IPR006096) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251286 control chromosomes (gnomAD). c.1498G>A (also known as p.Ala447Thr) has been reported in the literature in individuals affected with Congenital Hyperinsulinism (examples: Stanley_2000, Faletra_2013, and Hopkins_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23506826, 36239000, 10871207). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 6, 2024

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