Submissions for variant NM_152564.5(VPS13B):c.9530T>C (p.Leu3177Pro)

gnomAD frequency: 0.00008  dbSNP: rs199559979

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000154130	SCV000203794	uncertain significance	not provided	2013-12-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000264740	SCV000470840	uncertain significance	Cohen syndrome	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.
Invitae	RCV000264740	SCV000755383	uncertain significance	Cohen syndrome	2022-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3202 of the VPS13B protein (p.Leu3202Pro). This variant is present in population databases (rs199559979, 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: 167833). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Fulgent Genetics, Fulgent Genetics	RCV000264740	SCV000897411	uncertain significance	Cohen syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381488	SCV002694952	uncertain significance	Inborn genetic diseases	2020-12-19	criteria provided, single submitter	clinical testing	The c.9605T>C (p.L3202P) alteration is located in exon 52 (coding exon 51) of the VPS13B gene. This alteration results from a T to C substitution at nucleotide position 9605, causing the leucine (L) at amino acid position 3202 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000264740	SCV001461451	uncertain significance	Cohen syndrome	2020-01-24	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003150955	SCV003839213	uncertain significance	not specified	2022-08-24	no assertion criteria provided	clinical testing	DNA sequence analysis of the VPS13B gene demonstrated a sequence change, c.9605T>C, in exon 52 that results in an amino acid change, p.Leu3202Pro. This sequence change does not appear to have been previously described in individuals with VPS13B-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.013% in the European subpopulation (dbSNP rs199559979). The p.Leu3202Pro change affects a moderately conserved amino acid residue located in a domain of the VPS13B protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu3202Pro substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu3202Pro change remains unknown at this time.