Submissions for variant NM_152564.5(VPS13B):c.3G>A (p.Met1Ile)

dbSNP: rs1060499779

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000454311	SCV000538006	likely pathogenic	Abnormal brain morphology		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330683	SCV004039092	uncertain significance	not specified	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (p.Met11) is located in exon 1 of the encoded protein. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.3G>A has been reported in the literature in a family affected with Intellectual disability and microcephaly without classical Cohen syndrome (example: Karaca_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26539891). One submitter has cited clinical-significance assessments for this variant to ClinVar and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV003497850	SCV004295246	uncertain significance	Cohen syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the VPS13B mRNA. The next in-frame methionine is located at codon 11. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with clinical features of VPS13B-related conditions (PMID: 26539891). ClinVar contains an entry for this variant (Variation ID: 402220). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.