Submissions for variant NM_147127.5(EVC2):c.3660del (p.Ser1220fs)

gnomAD frequency: 0.00002  dbSNP: rs753581033

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669358	SCV000794105	pathogenic	Ellis-van Creveld syndrome	2017-09-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001214869	SCV001386574	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1220Argfs*3) in the EVC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the EVC2 protein. This variant is present in population databases (rs753581033, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with autosomal recessive Ellis-van Creveld syndrome (PMID: 12571802, 17024374, 19810119, 23220543). This variant is also known as c.3660delC. ClinVar contains an entry for this variant (Variation ID: 553833). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the EVC2 protein in which other variant(s) (p.Leu1265Tyrfs*2) have been determined to be pathogenic (PMID: 16404586). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001553071	SCV001773875	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 89 amino acids are lost and replaced with 2 incorrect amino acids (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 19810119, 17024374, 12571802, 19876929, 23220543)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000669358	SCV002599016	pathogenic	Ellis-van Creveld syndrome	2022-09-08	criteria provided, single submitter	clinical testing	Variant summary: EVC2 c.3660delC (p.Ser1220ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant allele was found at a frequency of 2e-05 in 250124 control chromosomes (gnomAD). c.3660delC has been reported in the literature in multiple individuals affected with Ellis-Van Creveld Syndrome, including homozygotes (Ruiz-Perez_2003, 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. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001214869	SCV002805346	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2022-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000669358	SCV000023705	pathogenic	Ellis-van Creveld syndrome	2003-03-01	no assertion criteria provided	literature only