Submissions for variant NM_152618.3(BBS12):c.1A>C (p.Met1Leu)

gnomAD frequency: 0.00004  dbSNP: rs750366365

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001243319	SCV001416468	uncertain significance	Bardet-Biedl syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the BBS12 mRNA. The next in-frame methionine is located at codon 3. This variant is present in population databases (rs750366365, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with BBS12-related conditions. ClinVar contains an entry for this variant (Variation ID: 551815). 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	RCV002530704	SCV003760153	uncertain significance	Inborn genetic diseases	2021-08-23	criteria provided, single submitter	clinical testing	The c.1A>C (p.M1?) alteration is located in coding exon 1 of the BBS12 gene and consists of a A to C substitution at nucleotide position 1. This changes the amino acid from a methionine to a (?) at the initiation codon. Sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame and are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003403546	SCV004110410	uncertain significance	BBS12-related disorder	2023-05-09	criteria provided, single submitter	clinical testing	The BBS12 c.1A>C variant is predicted to disrupt the translation initiation site (Start loss). However, an in-frame methionine (potential alternative start codon) is present at the third codon. This variant was documented in a family with recessive form of retinitis pigmentosa (Table S5 - Watson et al. 2014. PubMed ID: 25133751). This variant is reported in 0.049% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-123663048-A-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Counsyl	RCV000666963	SCV000791342	likely pathogenic	Bardet-Biedl syndrome 12	2017-05-08	flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356998	SCV001552316	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BBS12 p.M1? variant was not identified in the literature but was identified in dbSNP (ID: rs750366365) and ClinVar (classified as uncertain significance by Invitae and as likely pathogenic by Counsyl). The variant was identified in control databases in 31 of 282602 chromosomes at a frequency of 0.0001097 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.M1? variant results in the loss of the initiation codon however the next in-frame initiation codon occurs two codons downstream, therefore it is unclear how this may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000666963	SCV002082466	uncertain significance	Bardet-Biedl syndrome 12	2020-01-22	no assertion criteria provided	clinical testing