Submissions for variant NM_152618.3(BBS12):c.1198G>A (p.Val400Met)

gnomAD frequency: 0.00005  dbSNP: rs771136797

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000260403	SCV000332453	uncertain significance	not provided	2015-06-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000665039	SCV000789096	uncertain significance	Bardet-Biedl syndrome 12	2017-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000665039	SCV001307536	uncertain significance	Bardet-Biedl syndrome 12	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Pars Genome Lab	RCV000665039	SCV001736834	uncertain significance	Bardet-Biedl syndrome 12	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844109	SCV002104098	uncertain significance	not specified	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: BBS12 c.1198G>A (p.Val400Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251452 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BBS12 causing Bardet-Biedl Syndrome (7.6e-05 vs 0.00076), allowing no conclusion about variant significance. c.1198G>A has been reported in the literature in an individual affected with Bardet-Biedl Syndrome who carried the variant in the homozygous state in cis with a different potentially pathogenic variant (Billingsley_2010). This report does not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
New York Genome Center	RCV000665039	SCV002764583	uncertain significance	Bardet-Biedl syndrome 12	2021-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000665039	SCV002814188	uncertain significance	Bardet-Biedl syndrome 12	2022-01-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519090	SCV003197853	uncertain significance	Bardet-Biedl syndrome	2022-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 400 of the BBS12 protein (p.Val400Met). This variant is present in population databases (rs771136797, gnomAD 0.1%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20472660). ClinVar contains an entry for this variant (Variation ID: 281597). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
PreventionGenetics, part of Exact Sciences	RCV003930048	SCV004740001	uncertain significance	BBS12-related disorder	2024-02-08	criteria provided, single submitter	clinical testing	The BBS12 c.1198G>A variant is predicted to result in the amino acid substitution p.Val400Met. This variant was reported in the homozygous state in two siblings with Bardet-Biedl syndrome (Billingsley et al 2010. PubMed ID: 20472660). However, an additional homozygous variant in BBS12 as well as a single missense variant in BBS1 were also found in these siblings. This variant is reported in 0.099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.