Submissions for variant NM_152564.5(VPS13B):c.5663T>C (p.Ile1888Thr)

gnomAD frequency: 0.00004  dbSNP: rs779082817

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000300663	SCV000470815	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	RCV000501281	SCV000597885	uncertain significance	not specified	2017-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000300663	SCV001420599	uncertain significance	Cohen syndrome	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1913 of the VPS13B protein (p.Ile1913Thr). This variant is present in population databases (rs779082817, gnomAD 0.03%). 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: 361068). 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: "Benign"; 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	RCV003243114	SCV003940038	uncertain significance	Inborn genetic diseases	2023-04-25	criteria provided, single submitter	clinical testing	The c.5738T>C (p.I1913T) alteration is located in exon 34 (coding exon 33) of the VPS13B gene. This alteration results from a T to C substitution at nucleotide position 5738, causing the isoleucine (I) at amino acid position 1913 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000300663	SCV002082588	uncertain significance	Cohen syndrome	2020-03-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742404	SCV005365251	uncertain significance	VPS13B-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The VPS13B c.5663T>C variant is predicted to result in the amino acid substitution p.Ile1888Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% 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.