Submissions for variant NM_000159.4(GCDH):c.782C>T (p.Thr261Ile)

dbSNP: rs777494547

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803410	SCV000943280	uncertain significance	Glutaric aciduria, type 1	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with isoleucine at codon 261 of the GCDH protein (p.Thr261Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs777494547, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with GCDH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000803410	SCV001286370	uncertain significance	Glutaric aciduria, type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Neuberg Centre For Genomic Medicine, NCGM	RCV000803410	SCV005374774	uncertain significance	Glutaric aciduria, type 1		criteria provided, single submitter	clinical testing	The observed missense c.782C>T(p.Thr261Ile) variant in GCDH gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.001% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Uncertain significance (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 261 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Natera, Inc.	RCV000803410	SCV001455954	uncertain significance	Glutaric aciduria, type 1	2020-03-11	no assertion criteria provided	clinical testing