Submissions for variant NM_152564.5(VPS13B):c.1754G>A (p.Arg585His)

gnomAD frequency: 0.00005  dbSNP: rs773472945

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658259	SCV000780030	uncertain significance	not provided	2018-05-22	criteria provided, single submitter	clinical testing	The R585H variant in the VPS13B gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R585H variant is observed in 9/277056 (0.003%) alleles in large population cohorts, with no homozygotes observed (Lek et al., 2016). The R585H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R585H as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049937	SCV001214017	uncertain significance	Cohen syndrome	2022-09-07	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 585 of the VPS13B protein (p.Arg585His). This variant is present in population databases (rs773472945, gnomAD 0.02%). 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: 546393). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
CeGaT Center for Human Genetics Tuebingen	RCV000658259	SCV001746047	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001049937	SCV002079478	uncertain significance	Cohen syndrome	2021-07-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742558	SCV005356340	uncertain significance	VPS13B-related disorder	2024-06-30	no assertion criteria provided	clinical testing	The VPS13B c.1754G>A variant is predicted to result in the amino acid substitution p.Arg585His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.