Submissions for variant NM_152564.5(VPS13B):c.4262A>G (p.His1421Arg)

gnomAD frequency: 0.00008  dbSNP: rs371961155

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723627	SCV000113836	uncertain significance	not provided	2013-04-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000382355	SCV000470805	uncertain significance	Cohen 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, 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.
Genetic Services Laboratory, University of Chicago	RCV000081901	SCV000597884	uncertain significance	not specified	2015-10-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000382355	SCV000897407	uncertain significance	Cohen syndrome	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723627	SCV001155463	uncertain significance	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000382355	SCV003781788	uncertain significance	Cohen syndrome	2022-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1446 of the VPS13B protein (p.His1446Arg). This variant is present in population databases (rs371961155, 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: 95854). 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.
PreventionGenetics, part of Exact Sciences	RCV003390778	SCV004119589	uncertain significance	VPS13B-related disorder	2024-03-01	criteria provided, single submitter	clinical testing	The VPS13B c.4262A>G variant is predicted to result in the amino acid substitution p.His1421Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% 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.
Ambry Genetics	RCV004019572	SCV004978147	uncertain significance	Inborn genetic diseases	2021-08-02	criteria provided, single submitter	clinical testing	The c.4337A>G (p.H1446R) alteration is located in exon 29 (coding exon 28) of the VPS13B gene. This alteration results from a A to G substitution at nucleotide position 4337, causing the histidine (H) at amino acid position 1446 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.