ClinVar Miner

Submissions for variant NM_152618.3(BBS12):c.1507G>T (p.Val503Leu)

gnomAD frequency: 0.00006  dbSNP: rs374865012
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431828 SCV000532540 uncertain significance not provided 2016-10-17 criteria provided, single submitter clinical testing The V503L variant in the BBS12 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V503L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V503L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V503L as a variant of uncertain significance.
Invitae RCV000703463 SCV000832363 uncertain significance Bardet-Biedl syndrome 2022-03-20 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 503 of the BBS12 protein (p.Val503Leu). This variant is present in population databases (rs374865012, gnomAD 0.02%). 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: 389871). 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.
Fulgent Genetics, Fulgent Genetics RCV001828437 SCV002777917 uncertain significance Bardet-Biedl syndrome 12 2022-04-05 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003902604 SCV004719640 uncertain significance BBS12-related condition 2023-12-14 criteria provided, single submitter clinical testing The BBS12 c.1507G>T variant is predicted to result in the amino acid substitution p.Val503Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of European (Finnish) descent in gnomAD. Of note, a different variant impacting the same amino acid (p.Val503Met) has been reported in a patient with Bardet–Biedl syndrome (Patient A3227, Janssen et al. 2011. PubMed ID: 21052717). At this time, the clinical significance of the c.1507G>T (p.Val503Leu) variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000431828 SCV001549297 uncertain significance not provided no assertion criteria provided clinical testing The BBS12 p.V503L variant was not identified in the literature but was identified in dbSNP (ID: rs374865012) and ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 27 of 282844 chromosomes at a frequency of 0.00009546 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 4 of 25120 chromosomes (freq: 0.000159), European (non-Finnish) in 19 of 129160 chromosomes (freq: 0.000147), Other in 1 of 7220 chromosomes (freq: 0.000139), Latino in 2 of 35436 chromosomes (freq: 0.000056) and African in 1 of 24968 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.V503 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. RCV001828437 SCV002084740 uncertain significance Bardet-Biedl syndrome 12 2020-01-20 no assertion criteria provided clinical testing

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