Submissions for variant NM_152564.5(VPS13B):c.3116T>C (p.Met1039Thr)

gnomAD frequency: 0.00144  dbSNP: rs140015545

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000634126	SCV000755417	likely benign	Cohen syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000634126	SCV000899080	uncertain significance	Cohen syndrome	2021-03-30	criteria provided, single submitter	clinical testing	VPS13B NM_017890 exon 22 p.Met1039Thr (c.3116T>C): This variant has not been reported in the literature but is present in 0.4% (98/24028) African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs140015545). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV001797117	SCV002038827	uncertain significance	not provided	2020-10-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001816570	SCV002071433	uncertain significance	not specified	2021-07-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the VPS13B gene demonstrated a sequence change, c.3116T>C, in exon 22 that results in an amino acid change, p.Met1039Thr. This sequence change does not appear to have been previously described in patients with VPS13B-related disorders and has been described in the gnomAD database with a low population frequency of 0.039% (dbSNP rs140015545). The p.Met1039Thr change affects a poorly 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.Met1039Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Met1039Thr change remains unknown at this time. Homozygous and compound heterozygous mutations in VPS13B have been identified in patients with Cohen syndrome [MIM#216550], characterized by ID, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia and intermittent neutropenia.
Ambry Genetics	RCV002325219	SCV002607919	likely benign	Inborn genetic diseases	2024-05-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV001797117	SCV004158259	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	VPS13B: BP4
PreventionGenetics, part of Exact Sciences	RCV003928059	SCV004750876	likely benign	VPS13B-related disorder	2023-12-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).