Submissions for variant NM_000159.4(GCDH):c.1261G>A (p.Ala421Thr)

gnomAD frequency: 0.00061  dbSNP: rs151201155

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672042	SCV001360427	likely pathogenic	Glutaric aciduria, type 1	2022-02-23	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.1261G>A (p.Ala421Thr) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 150930 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.0018 in the gnomAD database (v3.1 dataset), including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (0.0035), allowing no conclusion about variant significance. The variant, c.1261G>A, has been reported in the literature in multiple compound heterozygous individuals affected with Glutaric Acidemia Type 1 (Christensen_2004, Tsai_2017, Wahab_2016, Dong_2020, Lin_2021, Guenzel_2021). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated decreased enzymatic activity both in patient derived fibroblasts (Christensen_2004) and in bacterial expression systems (Goodman_1998, Westover_2003), although the level of residual activity varied greatly between these experimental methods. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3), and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV000327109	SCV001820071	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	Published functional studies found A421T is associated with significantly reduced enzyme activity (PMID: 9711871, 12948740); Identified in individuals with glutaric aciduria type 1 in published literature, although clinical information was not provided (PMID: 9711871); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27672653, 28302372, 25087612, 23891399, 12948740, 28062662, 15505393, 32306145, 32005694, 34258142, 34344405, 9711871)
Revvity Omics, Revvity	RCV000672042	SCV002024228	pathogenic	Glutaric aciduria, type 1	2022-12-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672042	SCV002240721	pathogenic	Glutaric aciduria, type 1	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 421 of the GCDH protein (p.Ala421Thr). This variant is present in population databases (rs151201155, gnomAD 0.2%). This missense change has been observed in individual(s) with GCDH-related conditions (PMID: 27672653, 28302372). ClinVar contains an entry for this variant (Variation ID: 285973). 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 not expected to disrupt GCDH protein function with a negative predictive value of 80%. This variant disrupts the p.Ala421 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8900227, 15505393, 28438223). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000672042	SCV004198746	likely pathogenic	Glutaric aciduria, type 1	2024-03-27	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000672042	SCV005051787	pathogenic	Glutaric aciduria, type 1	2024-02-01	criteria provided, single submitter	curation
Eurofins Ntd Llc (ga)	RCV000327109	SCV000339215	uncertain significance	not provided	2016-02-13	flagged submission	clinical testing
Counsyl	RCV000672042	SCV000797101	uncertain significance	Glutaric aciduria, type 1	2018-01-11	flagged submission	clinical testing
GenomeConnect, ClinGen	RCV000672042	SCV002818336	not provided	Glutaric aciduria, type 1		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 06-18-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.