Submissions for variant NM_147127.5(EVC2):c.983G>A (p.Gly328Glu)

gnomAD frequency: 0.00004  dbSNP: rs370838180

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001151785	SCV001312955	uncertain significance	Ellis-van Creveld syndrome	2018-01-12	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.
Invitae	RCV002559463	SCV003250237	uncertain significance	Ellis-van Creveld syndrome; Curry-Hall syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 328 of the EVC2 protein (p.Gly328Glu). This variant is present in population databases (rs370838180, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with EVC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 904088). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV002558319	SCV003724632	uncertain significance	Inborn genetic diseases	2021-08-13	criteria provided, single submitter	clinical testing	The c.983G>A (p.G328E) alteration is located in exon 8 (coding exon 8) of the EVC2 gene. This alteration results from a G to A substitution at nucleotide position 983, causing the glycine (G) at amino acid position 328 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003953536	SCV004768110	uncertain significance	EVC2-related condition	2024-02-21	criteria provided, single submitter	clinical testing	The EVC2 c.983G>A variant is predicted to result in the amino acid substitution p.Gly328Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-5667264-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.