Submissions for variant NM_015910.7(WDPCP):c.677A>T (p.Glu226Val)

gnomAD frequency: 0.00001  dbSNP: rs774816454

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064039	SCV001228912	uncertain significance	Bardet-Biedl syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 226 of the WDPCP protein (p.Glu226Val). This variant is present in population databases (rs774816454, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with WDPCP-related conditions. ClinVar contains an entry for this variant (Variation ID: 858210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WDPCP protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002505639	SCV002801464	uncertain significance	Heart defect - tongue hamartoma - polysyndactyly syndrome; Bardet-Biedl syndrome 15	2022-03-17	criteria provided, single submitter	clinical testing
GeneDx	RCV003322848	SCV004028012	uncertain significance	not provided	2023-02-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015)
Ambry Genetics	RCV004963083	SCV005528211	likely benign	Inborn genetic diseases	2024-06-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Daryl Scott Lab, Baylor College of Medicine	RCV003405281	SCV005871358	uncertain significance	WDPCP-related disorder	2024-01-01	criteria provided, single submitter	clinical testing	PM2
PreventionGenetics, part of Exact Sciences	RCV003405281	SCV004116080	uncertain significance	WDPCP-related disorder	2024-01-25	no assertion criteria provided	clinical testing	The WDPCP c.677A>T variant is predicted to result in the amino acid substitution p.Glu226Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.034% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.