Submissions for variant NM_153717.3(EVC):c.469C>G (p.Pro157Ala)

gnomAD frequency: 0.00451  dbSNP: rs146729456

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178397	SCV000230470	likely benign	not specified	2015-01-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000341901	SCV000450143	likely benign	Ellis-van Creveld syndrome	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000878090	SCV001020939	benign	Ellis-van Creveld syndrome; Curry-Hall syndrome	2025-01-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001354236	SCV001473418	likely benign	not provided	2023-09-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001354236	SCV001885238	benign	not provided	2018-08-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000878090	SCV002811863	likely benign	Ellis-van Creveld syndrome; Curry-Hall syndrome	2021-10-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517732	SCV003748727	uncertain significance	Inborn genetic diseases	2021-08-12	criteria provided, single submitter	clinical testing	The c.469C>G (p.P157A) alteration is located in exon 4 (coding exon 4) of the EVC gene. This alteration results from a C to G substitution at nucleotide position 469, causing the proline (P) at amino acid position 157 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV001354236	SCV004147606	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	EVC: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV001354236	SCV005256689	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000341901	SCV001454790	benign	Ellis-van Creveld syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354236	SCV001548798	likely benign	not provided		no assertion criteria provided	clinical testing	The EVC p.Pro157Ala variant was not identified in the literature but was identified in dbSNP (ID: rs146729456), ClinVar (classified as likely benign by Illumina for Weyers Acrofacial Dysostosis and Ellis-van Creveld Syndrome, likely benign by EGL Genetic Diagnostics, and benign by Invitae) and LOVD 3.0 (classified as likely benign by VKGL data sharing initiative Nederland). The variant was identified in control databases in 1379 of 282748 chromosomes (7 homozygous) at a frequency of 0.004877 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 898 of 129070 chromosomes (freq: 0.006957), Ashkenazi Jewish in 72 of 10366 chromosomes (freq: 0.006946), Other in 49 of 7222 chromosomes (freq: 0.006785), European (Finnish) in 133 of 25122 chromosomes (freq: 0.005294), Latino in 167 of 35436 chromosomes (freq: 0.004713), African in 38 of 24966 chromosomes (freq: 0.001522) and South Asian in 22 of 30616 chromosomes (freq: 0.000719), but was not observed in the East Asian population. The p.Pro157 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001354236	SCV001799619	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001354236	SCV001972352	likely benign	not provided		no assertion criteria provided	clinical testing