Submissions for variant NM_147127.5(EVC2):c.3121C>T (p.Gln1041Ter)

gnomAD frequency: 0.00002  dbSNP: rs376133710

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001228575	SCV001400978	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2023-03-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 446685). This premature translational stop signal has been observed in individual(s) with short-rib polydactyly syndrome (PMID: 29068549). This variant is present in population databases (rs376133710, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Gln1041*) in the EVC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EVC2 are known to be pathogenic (PMID: 17024374, 19810119, 19876929).
PreventionGenetics, part of Exact Sciences	RCV003979919	SCV004790709	likely pathogenic	EVC2-related disorder	2023-11-24	criteria provided, single submitter	clinical testing	The EVC2 c.3121C>T variant is predicted to result in premature protein termination (p.Gln1041*). This variant has been reported in an individual with short rib-polydactyly syndrome, type 4 (SRPS IV, Table S3, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Nonsense variants in EVC2 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987575	SCV004804484	pathogenic	Ellis-van Creveld syndrome	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: EVC2 c.3121C>T (p.Gln1041X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 249074 control chromosomes (gnomAD). c.3121C>T has been reported in the literature in an individual affected with short-rib polydactyly syndrome (Zhang_2018). The following publication has been ascertained in the context of this evaluation (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446685). Based on the evidence outlined above, the variant was classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV003987575	SCV004847198	pathogenic	Ellis-van Creveld syndrome	2023-08-01	criteria provided, single submitter	clinical testing
Dan Cohn Lab, University Of California Los Angeles	RCV000516007	SCV000612118	likely pathogenic	Type IV short rib polydactyly syndrome	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516007	SCV001479554	likely pathogenic	Type IV short rib polydactyly syndrome		no assertion criteria provided	research