ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11660T>C (p.Ile3887Thr)

gnomAD frequency: 0.00002  dbSNP: rs45630562
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000600976 SCV000713823 uncertain significance not specified 2018-01-17 criteria provided, single submitter clinical testing The p.Ile3888Thr variant in ALMS1 has been reported in 3 individuals with Alstro m syndrome, two of whom carried a pathogenic variant on the other allele. Howeve r, the third individual carried a truncating variant on the same copy (in cis) a s the p.Ile3888Thr variant, and had another pathogenic variant on the other copy of the gene (Marshall 2007). This variant has also been identified in 5/111172 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs45630562); though this frequency is not high enough t o rule out a pathogenic role. Furthermore, isoleucine (Ile) at position 3888 is not conserved in mammals or evolutionarily distant species and 1 mammal (Gibbon) carries a threonine (Thr) at this position, raising the possibility that this c hange may be tolerated. Additional computational prediction tools support that t he variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ile3888Thr variant is uncertain. ACMG/AMP criteria applied: PM3_Strong, PM2, PP1, BP2, BP4.
GeneDx RCV001755989 SCV001988340 uncertain significance not provided 2019-04-10 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; This variant is associated with the following publications: (PMID: 25296579, 25846608, 17594715)
Fulgent Genetics, Fulgent Genetics RCV001834935 SCV002787717 uncertain significance Alstrom syndrome 2021-09-16 criteria provided, single submitter clinical testing
Invitae RCV001834935 SCV003454205 uncertain significance Alstrom syndrome 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 3888 of the ALMS1 protein (p.Ile3888Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs45630562, gnomAD 0.004%). This missense change has been observed in individuals with Alstrom syndrome (PMID: 17594715). ClinVar contains an entry for this variant (Variation ID: 506260). 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 RCV000600976 SCV003844323 uncertain significance not specified 2023-02-28 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.11657T>C (p.Ile3886Thr), also known as c.11663T>C (p.Ile3888Thr), results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248850 control chromosomes (gnomAD). c.11657T>C has been reported in the literature in individuals affected with Alstrom Syndrome (e.g. Marshall_2007, Pereiro_2011, Ozanturk_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc. RCV001834935 SCV002079022 uncertain significance Alstrom syndrome 2021-08-18 no assertion criteria provided clinical testing

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