Submissions for variant NM_152564.5(VPS13B):c.1627A>G (p.Thr543Ala)

gnomAD frequency: 0.00004  dbSNP: rs372625091

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000492966	SCV000582950	uncertain significance	not provided	2024-06-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793866	SCV000933243	uncertain significance	Cohen syndrome	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 543 of the VPS13B protein (p.Thr543Ala). This variant is present in population databases (rs372625091, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 430203). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). 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.
Ambry Genetics	RCV003278843	SCV003958313	uncertain significance	Inborn genetic diseases	2023-03-20	criteria provided, single submitter	clinical testing	The c.1627A>G (p.T543A) alteration is located in exon 12 (coding exon 11) of the VPS13B gene. This alteration results from a A to G substitution at nucleotide position 1627, causing the threonine (T) at amino acid position 543 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000793866	SCV004031214	uncertain significance	Cohen syndrome	2023-06-26	criteria provided, single submitter	clinical testing	The VPS13B c.1627A>G (p.Thr543Ala) missense change has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Cohen syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Natera, Inc.	RCV000793866	SCV001454808	uncertain significance	Cohen syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003392324	SCV004119955	uncertain significance	VPS13B-related disorder	2024-05-13	no assertion criteria provided	clinical testing	The VPS13B c.1627A>G variant is predicted to result in the amino acid substitution p.Thr543Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.