Submissions for variant NM_147127.5(EVC2):c.619G>T (p.Asp207Tyr)

gnomAD frequency: 0.00001  dbSNP: rs761707323

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388085	SCV001588932	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2023-05-21	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with autosomal recessive Ellis-van Creveld syndrome (PMID: 19251731, 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 446663). This variant is present in population databases (rs761707323, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 207 of the EVC2 protein (p.Asp207Tyr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000667862	SCV005202838	likely pathogenic	Ellis-van Creveld syndrome	2024-07-24	criteria provided, single submitter	clinical testing	Variant summary: EVC2 c.619G>T (p.Asp207Tyr) results in a non-conservative amino acid change in 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 4e-06 in 251486 control chromosomes. c.619G>T has been reported in the literature as compound heterozygous genotype in individuals affected with clinical features of Ellis-van Creveld syndrome (Sund_2009, Zhang_2018). These data indicate that the variant is likely to be associated with disease. 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: 446663). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV000516039	SCV000612084	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
Dan Cohn Lab, University Of California Los Angeles	RCV000667862	SCV000612088	pathogenic	Ellis-van Creveld syndrome	2017-06-01	no assertion criteria provided	research
Counsyl	RCV000667862	SCV000792373	uncertain significance	Ellis-van Creveld syndrome	2017-06-15	flagged submission	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000667862	SCV001479417	likely pathogenic	Ellis-van Creveld syndrome		no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516039	SCV001479599	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003915444	SCV004729374	pathogenic	EVC2-related disorder	2023-12-12	no assertion criteria provided	clinical testing	The EVC2 c.619G>T variant is predicted to result in the amino acid substitution p.Asp207Tyr. This variant has been reported in the compound heterozygous state in individuals with autosomal recessive Ellis-van Creveld syndrome and asphyxiating thoracic dystrophy (Sund et al. 2009. PubMed ID: 19251731; Table S2, Zhang et al. 2018. PubMed ID: 29068549). In addition, we have observed this variant along with a nonsense variant in an individual with a clinical diagnosis of Ellis-van Creveld syndrome (PreventionGenetics internal data). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.