Submissions for variant NM_147127.5(EVC2):c.2739G>C (p.Lys913Asn)

gnomAD frequency: 0.00007  dbSNP: rs180747811

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001560130	SCV001782477	uncertain significance	not provided	2020-12-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29068549)
Fulgent Genetics, Fulgent Genetics	RCV002476033	SCV002788893	uncertain significance	Ellis-van Creveld syndrome; Curry-Hall syndrome	2022-03-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002476033	SCV003006228	uncertain significance	Ellis-van Creveld syndrome; Curry-Hall syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 913 of the EVC2 protein (p.Lys913Asn). This variant is present in population databases (rs180747811, gnomAD 0.2%). 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: 446693). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155219	SCV003844731	uncertain significance	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: EVC2 c.2739G>C (p.Lys913Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251470 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EVC2 causing Ellis-van Creveld syndrome (0.00012 vs 0.0029), allowing no conclusion about variant significance. c.2739G>C has been reported in the literature in at least one individual affected with Ellis-van Creveld syndrome. 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Dan Cohn Lab, University Of California Los Angeles	RCV000516048	SCV000612130	uncertain significance	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516048	SCV001479708	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research