Submissions for variant NM_152564.5(VPS13B):c.560G>A (p.Arg187His)

gnomAD frequency: 0.00008  dbSNP: rs150941426

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000501218	SCV000597911	uncertain significance	not specified	2015-11-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000658167	SCV000779938	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing	The R187H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R187H variant is observed in 13/30782 (0.04%) alleles from individuals of South Asian background (Lek et al., 2016). The R187H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821626	SCV000962395	uncertain significance	Cohen syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 187 of the VPS13B protein (p.Arg187His). This variant is present in population databases (rs150941426, gnomAD 0.04%). 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: 437253). 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	RCV002524331	SCV003732955	uncertain significance	Inborn genetic diseases	2021-12-28	criteria provided, single submitter	clinical testing	The c.560G>A (p.R187H) alteration is located in exon 5 (coding exon 4) of the VPS13B gene. This alteration results from a G to A substitution at nucleotide position 560, causing the arginine (R) at amino acid position 187 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000821626	SCV001454217	uncertain significance	Cohen syndrome	2020-04-15	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742468	SCV005365988	uncertain significance	VPS13B-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The VPS13B c.560G>A variant is predicted to result in the amino acid substitution p.Arg187His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.