Submissions for variant NM_153717.3(EVC):c.89C>T (p.Pro30Leu)

gnomAD frequency: 0.00121  dbSNP: rs886044558

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000398177	SCV000345425	uncertain significance	not provided	2016-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV000536411	SCV000634730	benign	Ellis-van Creveld syndrome; Curry-Hall syndrome	2024-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000398177	SCV000883812	uncertain significance	not provided	2017-07-14	criteria provided, single submitter	clinical testing	The p.Pro30Leu has not been reported in the scientific literature and gene specific variant databases. However, the p.Pro30Leu is listed in ClinVar with current classification of uncertain significance (Variation ID 290794). This variant is listed in the Genome Aggregation Consortium Browser with an overall allele frequency of 0.12 percent (identified on 31 out of 25,982 chromosomes) but it was indicated as a low quality site. Additionally, proline 30 is moderately conserved considering 12 species (Alamut software v2.9.0) and computational prediction programs do not agree in their assessment of an impact of this variant on the protein (SIFT: tolerated, PolyPhen-2: benign, and MutationTaster: disease causing).
Illumina Laboratory Services, Illumina	RCV001153149	SCV001314411	uncertain significance	Ellis-van Creveld syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000398177	SCV001805399	likely benign	not provided	2019-04-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000398177	SCV004147603	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479096	SCV004223312	uncertain significance	not specified	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: EVC c.89C>T (p.Pro30Leu) 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 0.001 in 146640 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database (v3.1). To our knowledge, no occurrence of c.89C>T in individuals affected with Ellis-van Creveld syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters have classified the variant as uncertain significance and two classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003977813	SCV004786319	likely benign	EVC-related condition	2023-10-09	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001153149	SCV001462212	uncertain significance	Ellis-van Creveld syndrome	2019-11-11	no assertion criteria provided	clinical testing