ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.12086T>C (p.Leu4029Pro)

gnomAD frequency: 0.00010  dbSNP: rs372910832
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000813092 SCV000953430 uncertain significance Alstrom syndrome 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4030 of the ALMS1 protein (p.Leu4030Pro). This variant is present in population databases (rs372910832, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 656629). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx RCV001556167 SCV001777698 uncertain significance not provided 2020-11-17 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In addition, in silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002345849 SCV002650585 uncertain significance Cardiovascular phenotype 2021-06-07 criteria provided, single submitter clinical testing The p.L4030P variant (also known as c.12089T>C), located in coding exon 19 of the ALMS1 gene, results from a T to C substitution at nucleotide position 12089. The leucine at codon 4030 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and proline is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV000813092 SCV002079051 uncertain significance Alstrom syndrome 2021-01-19 no assertion criteria provided clinical testing

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