Submissions for variant NM_153717.3(EVC):c.1868T>C (p.Leu623Pro)

gnomAD frequency: 0.00001  dbSNP: rs1373632260

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668661	SCV000793295	uncertain significance	Ellis-van Creveld syndrome	2017-08-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001333014	SCV001525492	uncertain significance	Curry-Hall syndrome	2019-08-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855505	SCV002236742	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 623 of the EVC protein (p.Leu623Pro). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of Ellis-van Creveld syndrome (PMID: 18947413, 19810119; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553254). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EVC protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668661	SCV004029931	pathogenic	Ellis-van Creveld syndrome	2023-07-18	criteria provided, single submitter	clinical testing	Variant summary: EVC c.1868T>C (p.Leu623Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-06 in 156316 control chromosomes (i.e., 1 heterozygote; gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1868T>C has been reported in the literature in multiple homozygous individuals affected with features of Ellis-van Creveld syndrome, including limb and cardiac anomalies, and the variant has been shown to segregate with disease in related individuals (e.g., Ulucan_2008, Valencia_2009). These data indicate that the variant is very 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: 18947413, 19810119). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: one submitter classified the variant as pathogenic, and two submitters classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.