Submissions for variant NM_147127.5(EVC2):c.2848C>T (p.Arg950Trp)

gnomAD frequency: 0.00012  dbSNP: rs137852928

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244422	SCV001417642	uncertain significance	Ellis-van Creveld syndrome; Curry-Hall syndrome	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 950 of the EVC2 protein (p.Arg950Trp). This variant is present in population databases (rs137852928, gnomAD 0.2%). This missense change has been observed in individual(s) with Ellis–van Creveld syndrome (PMID: 12468274, 23220543, 32369273). This variant is also known as Arg870Trp. ClinVar contains an entry for this variant (Variation ID: 3387). 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. 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.
Myriad Genetics, Inc.	RCV000003554	SCV002060244	uncertain significance	Ellis-van Creveld syndrome	2021-10-01	criteria provided, single submitter	clinical testing	NM_147127.4(EVC2):c.2848C>T(R950W) is a missense variant classified as a variant of uncertain significance in the context of EVC2-related Ellis-van Creveld syndrome. R950W has been observed in cases with relevant disease (PMID: 12468274, 23220543, 32369273). Functional assessments of this variant are not available in the literature. R950W has been observed in population frequency databases (gnomAD: ASJ 0.17%). In summary, there is insufficient evidence to classify NM_147127.4(EVC2):c.2848C>T(R950W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV001244422	SCV002781080	uncertain significance	Ellis-van Creveld syndrome; Curry-Hall syndrome	2022-01-06	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003554	SCV005399117	uncertain significance	Ellis-van Creveld syndrome	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function is a known mechanisms of disease in this gene and are associated with recessive Ellis-van Creveld syndrome (MIM#225500). Gain of function and dominant negative is likely the mechanism associated with dominant Weyers acrofacial dysostosis(MIM#193530) (PMID: 19810119). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (41 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (18 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as VUS in ClinVar. It has also been reported in cis with p.(Gln1089*) in two individuals with Ellis-van Creveld syndrome (PMID: 12468274, 23220543). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV005054133	SCV005687920	uncertain significance	not provided	2024-07-31	criteria provided, single submitter	clinical testing	Identified in a patient with Ellis-van Creveld syndrome who also harbored a homozygous pathogenic variant on the same EVC2 allele (in cis) (PMID: 12468274); Reported along with two additional variants in the EVC2 gene in a patient with short stature, postaxial polydactyly, short ribs, and anteriorly placed anus in the published literature; however, segregation information was not provided (PMID: 23220543); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32369273, 33452237, 12468274, 23220543, 30476936)
OMIM	RCV000003554	SCV000023712	pathogenic	Ellis-van Creveld syndrome	2002-12-01	no assertion criteria provided	literature only