ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11708G>A (p.Arg3903Gln) (rs201673771)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766766 SCV000530107 uncertain significance not provided 2021-08-19 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
Genetic Services Laboratory,University of Chicago RCV000434472 SCV000593116 uncertain significance not specified 2016-08-25 criteria provided, single submitter clinical testing
Invitae RCV000634782 SCV000756125 uncertain significance Alstrom syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 3904 of the ALMS1 protein (p.Arg3904Gln). The arginine residue ismoderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs201673771, ExAC 0.08%). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 387921). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000434472 SCV000966364 likely benign not specified 2018-07-17 criteria provided, single submitter clinical testing The p.Arg3904Gln variant in ALMS1 is classified as likely benign due to a lack o f conservation across species, including mammals. Of note, golden hamster, mouse and rat have a glutamine (Gln) at this position. It has been identified in 119/ 126668 European chromosomes by the Genome Aggregation Database (gnomAD, http://g, dbSNP rs201673771). ACMG/AMP Criteria applied: BP4_Str ong, BS1_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000434472 SCV001774679 uncertain significance not specified 2021-07-27 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.11705G>A (p.Arg3902Gln) results in a 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 0.0005 in 250142 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.0005 vs 0.0018), allowing no conclusion about variant significance. c.11705G>A has been reported in the literature in one individual with a suspicion of Alstrm Syndrome (Marshall_2015). The report does not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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