Submissions for variant NM_147127.5(EVC2):c.3265C>T (p.Gln1089Ter)

gnomAD frequency: 0.00008  dbSNP: rs137852927

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799858	SCV000939540	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1089*) 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). This variant is present in population databases (rs137852927, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Ellis-van Creveld syndrome (PMID: 12468274, 23220543). This variant is also known as C3754T (Q1009X). ClinVar contains an entry for this variant (Variation ID: 3386). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000003553	SCV000967782	pathogenic	Ellis-van Creveld syndrome	2018-10-10	criteria provided, single submitter	clinical testing	The p.Gln1089X variant in EVC2 has been reported in the homozygous state in one individual with Ellis-van Creveld syndrome (Galdzicka 2002). It has also been id entified in 0.15% (15/9850) of European chromosomes by gnomAD (http://gnomad.bro adinstitute.org). This nonsense variant leads to a premature termination codon a t position 1089, which is predicted to lead to a truncated or absent protein. Bi allelic loss of function variants in EVC2 have been reported as disease causing in several individuals with Ellis-van Creveld syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Ellis-van Creveld syndrome based on a case observation and the predicted impact on the pr otein. ACMG/AMP criteria applied: PVS1, PP4, PM3_Supporting.
Myriad Genetics, Inc.	RCV000003553	SCV001193772	pathogenic	Ellis-van Creveld syndrome	2019-12-20	criteria provided, single submitter	clinical testing	NM_147127.4(EVC2):c.3265C>T(Q1089*) is classified as pathogenic in the context of EVC2-related Ellis-van Creveld syndrome. Sources cited for classification include the following: PMID 23220543 and 12468274. Classification of NM_147127.4(EVC2):c.3265C>T(Q1089*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Ambry Genetics	RCV001265673	SCV001443840	pathogenic	Inborn genetic diseases	2017-12-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000799858	SCV002813111	pathogenic	Ellis-van Creveld syndrome; Curry-Hall syndrome	2024-03-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003553	SCV005399114	pathogenic	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 Pathogenic. 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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (20 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in both homozygous and compound heterozgyous individuals with Ellis-van Creveld syndrome (PMID: 12468274, 23220543). It has also been reported multiple times as pathogenic in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV005054132	SCV005687919	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19876929, 25525159, 23220543, 12468274, 31980526, 34682862, 38163170, 30476936, 31428121)
OMIM	RCV000003553	SCV000023711	pathogenic	Ellis-van Creveld syndrome	2002-12-01	no assertion criteria provided	literature only