ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.9389C>G (p.Pro3130Arg) (rs200586877)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV000445473 SCV000536986 likely benign Monogenic diabetes 2019-01-25 criteria provided, single submitter research ACMG criteria: BP4 (REVEL 0.037 + 7 predictors), BP1 (missense variant when truncating case disease)=likely benign
Phosphorus, Inc. RCV000577939 SCV000679929 uncertain significance Alstrom syndrome 2017-08-01 criteria provided, single submitter clinical testing
Invitae RCV000577939 SCV000832537 uncertain significance Alstrom syndrome 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 3131 of the ALMS1 protein (p.Pro3131Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs200586877, ExAC 0.02%). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 393378). 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: "Not Available"; 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193867 SCV001363020 uncertain significance not specified 2019-02-25 criteria provided, single submitter clinical testing Variant summary: The variant, ALMS1 c.9386C>G (p.Pro3129Arg, also known as c.9392C>G) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 277096 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00016 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.9386C>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Uncertain Significance X2 ; Likely benign X1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001193867 SCV001365712 uncertain significance not specified 2020-01-24 criteria provided, single submitter clinical testing The p.Pro3131Arg variant in ALMS1 has not been previously reported in individuals with hearing loss, but has been identified in 0.03% (46/128626) of European chromosomes by gnomAD ( This variant has also been reported in ClinVar (Variation ID 393378). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4.
GeneDx RCV001552478 SCV001773167 uncertain significance not provided 2021-04-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV000577939 SCV001453033 uncertain significance Alstrom syndrome 2020-09-16 no assertion criteria provided clinical testing

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