Submissions for variant NM_000159.4(GCDH):c.647C>T (p.Ser216Leu)

gnomAD frequency: 0.00001  dbSNP: rs1449724176

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001564950	SCV001788199	uncertain significance	not provided	2019-06-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32240488, 32508882)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001832769	SCV002240542	pathogenic	Glutaric aciduria, type 1	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 216 of the GCDH protein (p.Ser216Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 32240488; Invitae). ClinVar contains an entry for this variant (Variation ID: 1200052). 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 GCDH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271661	SCV002555780	uncertain significance	not specified	2022-06-09	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.647C>T (p.Ser216Leu) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of 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 8e-06 in 251338 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.647C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Glutaric Acidemia Type 1 (example Kurkina_2020). These data do not allow a strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as VUS and one as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV001832769	SCV003814496	uncertain significance	Glutaric aciduria, type 1	2021-09-28	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV001832769	SCV003923326	likely pathogenic	Glutaric aciduria, type 1		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.647C>T in Exon 8 of the GCDH gene that results in the amino acid substitution p.Ser216Leu was identified. The observed variant has a minor allele frequency of 0.00001/% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic,UncertainSignificance,ConflictingInterpretations(variant ID 1200052). This variant has been observed in many individuals affected with Glutaricaciduria, type I reported by (E H, Liang L, Zhang H et al., 2021). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Natera, Inc.	RCV001832769	SCV002086970	uncertain significance	Glutaric aciduria, type 1	2020-09-11	no assertion criteria provided	clinical testing