Submissions for variant NM_153717.3(EVC):c.8G>C (p.Arg3Pro)

gnomAD frequency: 0.00195  dbSNP: rs756852655

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724435	SCV000224706	uncertain significance	not provided	2014-12-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000173582	SCV000594605	uncertain significance	not specified	2016-08-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724435	SCV000603496	uncertain significance	not provided	2020-07-04	criteria provided, single submitter	clinical testing	The EVC c.8G>C; p.Arg3Pro (rs756852655), to our knowledge, is not described in the medical literature but is reported as a variant of uncertain clinical significance in ClinVar (Variation ID 193508) and is observed in the general population at an overall allele frequency of 0.17% (45/26668 alleles) in the Genome Aggregation Database. The arginine at codon 3 is weakly conserved and computational algorithms (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure and/or function. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. Pathogenic EVC variants are associated with autosomal recessive Ellis-van Creveld syndrome (MIM:225500) and autosomal dominant Weyers acrodental dysostosis (MIM:193530).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085964	SCV000758483	likely benign	Ellis-van Creveld syndrome; Curry-Hall syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001153146	SCV001314408	uncertain significance	Ellis-van Creveld syndrome	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.
GeneDx	RCV000724435	SCV001765196	likely benign	not provided	2020-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002516592	SCV003689028	uncertain significance	Inborn genetic diseases	2021-07-15	criteria provided, single submitter	clinical testing	The c.8G>C (p.R3P) alteration is located in exon 1 (coding exon 1) of the EVC gene. This alteration results from a G to C substitution at nucleotide position 8, causing the arginine (R) at amino acid position 3 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000724435	SCV004811205	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173582	SCV005203846	likely benign	not specified	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: EVC c.8G>C (p.Arg3Pro) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 1012094 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in EVC causing Ellis-van Creveld syndrome phenotype. c.8G>C has been reported in the literature as a heterozygous genotype in at-least two individuals within a cohort with known COL1A1/A2 gene variants and a diagnosis of Osteogenesis Imperfecta (OI) (Andersson_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Ellis-van Creveld syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32234057). ClinVar contains an entry for this variant (Variation ID: 193508). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV001153146	SCV001462211	uncertain significance	Ellis-van Creveld syndrome	2019-11-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003975261	SCV004786879	likely benign	EVC-related disorder	2022-06-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).