Submissions for variant NM_152564.5(VPS13B):c.8384T>C (p.Ile2795Thr)

dbSNP: rs120074155

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002961	SCV001417780	uncertain significance	Cohen syndrome	2022-09-13	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 2820 of the VPS13B protein (p.Ile2820Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Cohen syndrome, and has been shown to co-segregate on the same chromosome with a known pathogenic variant (c.9260dup, also known as c.9258_9259insT) in the Old Order Amish population (PMID: 15211651, 17383910, 19006247). ClinVar contains an entry for this variant (Variation ID: 2827). 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 not 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	RCV002512689	SCV003732712	uncertain significance	Inborn genetic diseases	2022-06-17	criteria provided, single submitter	clinical testing	The c.8459T>C (p.I2820T) alteration is located in exon 46 (coding exon 45) of the VPS13B gene. This alteration results from a T to C substitution at nucleotide position 8459, causing the isoleucine (I) at amino acid position 2820 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM	RCV000002961	SCV000023119	pathogenic	Cohen syndrome	2004-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000002961	SCV000297976	not provided	Cohen syndrome		no assertion provided	literature only
Natera, Inc.	RCV000002961	SCV002082678	uncertain significance	Cohen syndrome	2020-04-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742208	SCV005361384	uncertain significance	VPS13B-related disorder	2024-04-29	no assertion criteria provided	clinical testing	The VPS13B c.8384T>C variant is predicted to result in the amino acid substitution p.Ile2795Thr. This variant is also known as c.8459T>C in the literature. This variant has been reported in the homozygous state along with another homozygous loss-of-function variant (c.9185dupT) in multiple individuals with Cohen syndrome from the Ohio Geauga Amish community (Falk et al. 2004. PubMed ID: 15211651; Table 1, Taban et al. 2007. PubMed ID: 17383910; Li et al. 2018. PubMed ID: 29985682). This variant has not been reported in a large population database, indicating this variant is rare. Functional studies did not support the pathogenicity of this variant (Zorn et al. 2022. PubMed ID: 35690661). Although we suspect that this variant may be benign, the clinical significance of this variant is classified as uncertain at this time due to insufficient functional and genetic evidence.