Submissions for variant NM_153717.3(EVC):c.1500G>A (p.Met500Ile)

gnomAD frequency: 0.00163  dbSNP: rs149898884

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003159658	SCV000726840	uncertain significance	not provided	2024-12-23	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29068549)
Counsyl	RCV000673759	SCV000798997	uncertain significance	Ellis-van Creveld syndrome	2018-04-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000878646	SCV001021582	likely benign	Ellis-van Creveld syndrome; Curry-Hall syndrome	2024-12-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782417	SCV005394469	uncertain significance	not specified	2024-09-13	criteria provided, single submitter	clinical testing	Variant summary: EVC c.1500G>A (p.Met500Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 279744 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EVC causing Ellis-van Creveld syndrome, however the data suggest that the variant could be a benign polymorphism. c.1500G>A has been reported in the literature in individuals affected with Ellis-van Creveld syndrome as a compound heterozygous genotype (e.g. Zhang_2018) or as an unreported polymorphism (e.g. Sund_2009). This report does 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 publications have been ascertained in the context of this evaluation (PMID: 19251731, 29068549). ClinVar contains an entry for this variant (Variation ID: 446659). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000878646	SCV005658314	uncertain significance	Ellis-van Creveld syndrome; Curry-Hall syndrome	2024-04-04	criteria provided, single submitter	clinical testing
Dan Cohn Lab, University Of California Los Angeles	RCV000673759	SCV000612077	pathogenic	Ellis-van Creveld syndrome	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000673759	SCV001479592	likely pathogenic	Ellis-van Creveld syndrome		no assertion criteria provided	research
Natera, Inc.	RCV000673759	SCV002083031	likely benign	Ellis-van Creveld syndrome	2020-02-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905290	SCV004722965	likely benign	EVC-related disorder	2022-10-28	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).