Submissions for variant NM_033305.3(VPS13A):c.2201G>A (p.Ser734Asn)

gnomAD frequency: 0.00061  dbSNP: rs117320408

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000347795	SCV000480757	uncertain significance	Chorea-acanthocytosis	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.
Athena Diagnostics Inc	RCV000518783	SCV000616243	uncertain significance	not specified	2017-03-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000347795	SCV000897529	uncertain significance	Chorea-acanthocytosis	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001562536	SCV001785313	likely benign	not provided	2020-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV001562536	SCV003500029	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 734 of the VPS13A protein (p.Ser734Asn). This variant is present in population databases (rs117320408, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VPS13A-related conditions. ClinVar contains an entry for this variant (Variation ID: 367364). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV002523807	SCV003706053	likely benign	Inborn genetic diseases	2021-09-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CeGaT Center for Human Genetics Tuebingen	RCV001562536	SCV004157845	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	VPS13A: PM2, BP4
Natera, Inc.	RCV000347795	SCV001452753	likely benign	Chorea-acanthocytosis	2020-06-05	no assertion criteria provided	clinical testing