Submissions for variant NM_152564.5(VPS13B):c.11338G>T (p.Val3780Leu)

gnomAD frequency: 0.00021  dbSNP: rs138565077

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000263082	SCV000470863	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.
CeGaT Center for Human Genetics Tuebingen	RCV000513155	SCV000609320	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000263082	SCV000755397	uncertain significance	Cohen syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3805 of the VPS13B protein (p.Val3805Leu). This variant is present in population databases (rs138565077, 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: 361096). 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 expected to disrupt VPS13B 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	RCV002450932	SCV002614496	uncertain significance	Inborn genetic diseases	2023-05-02	criteria provided, single submitter	clinical testing	The c.11413G>T (p.V3805L) alteration is located in exon 59 (coding exon 58) of the VPS13B gene. This alteration results from a G to T substitution at nucleotide position 11413, causing the valine (V) at amino acid position 3805 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252625	SCV001428386	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000263082	SCV001454484	uncertain significance	Cohen syndrome	2020-01-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000513155	SCV001549309	uncertain significance	not provided		no assertion criteria provided	clinical testing	The VPS13B p.Val3805Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs138565077) and in ClinVar (classified as a VUS by Inviate, Illumina and Praxis fuer Humangenetik Tuebingen). The variant was also identified in control databases in 56 of 282756 chromosomes at a frequency of 0.000198 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 12 of 35404 chromosomes (freq: 0.000339), European (non-Finnish) in 43 of 129138 chromosomes (freq: 0.000333) and African in 1 of 24956 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Val3805 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003418080	SCV004114726	uncertain significance	VPS13B-related disorder	2024-05-31	no assertion criteria provided	clinical testing	The VPS13B c.11338G>T variant is predicted to result in the amino acid substitution p.Val3780Leu. 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.