ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.11644C>T (p.His3882Tyr) (rs142278066)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229716 SCV000290068 uncertain significance Alstrom syndrome 2019-11-07 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 3882 of the ALMS1 protein (p.His3882Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs142278066, ExAC 0.2%) This variant has been reported in the literature in individuals affected with an ALMS1-related disease (PMID: 18154657, 28502102). However, in one of these individuals the variant was found to co-occur with 2 pathogenic variants in the BBS2 gene (PMID: 28502102). ClinVar contains an entry for this variant (Variation ID: 240979). 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: "Deleterious"; 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.
GeneDx RCV000413261 SCV000491552 uncertain significance not provided 2018-04-13 criteria provided, single submitter clinical testing The H3882Y variant of uncertain significance in the ALMS1 gene has been reported previously in one individual with Alstrom syndrome who also harbored another ALMS1 variant located on the opposite allele (in trans) (Joy et al., 2007). However, the H3882Y variant is observed in 218/126250 (0.2%) alleles from individuals of European (non-Finnish) ancestry and in 21/30776 (0.07%) alleles from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Functional studies did not show a difference in transcript processing when cells with H3882Y were compared to wild type cells (Alvarez-Satta et al., 2017). Nevertheless, the H3882Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825113 SCV000966368 likely benign not specified 2018-10-04 criteria provided, single submitter clinical testing The p.His3880Tyr variant is classifed as likely benign because it has been ident ified in 0.17% (218/126250) of European chromosomes by gnomAD (http://gnomad.bro adinstitute.org), and computational prediction tools and conservation analysis s uggest that this variant may not impact the protein. Furthermore, although this variant has been reported in two individuals with features of Alstrom syndrome, both individuals harbored pathogenic variants in BBS1 and BBS2 indicating a diag nosis of Bardet-Biedl syndrome (Joy 2007, Chen 2017, Alvarez-Satta 2017). In vi tro functional studies performed in patient fibroblast cells indicate that the v ariant did not have an effect on the protein function (Chen 2017, Alvarez-Satta 2017). This variant is reported in ClinVar (Variation ID: 240979). In summary, t his variant meets criteria to be classified as likely benign. ACMG/AMP Criteria applied: BS1_Supporting, BP4, BP5, BS3_Supporting.
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001172499 SCV001335552 likely benign Monogenic diabetes 2019-02-15 criteria provided, single submitter research ACMG criteria: BP4 (REVEL 0.042 + 5 predictors), BP1 (missense in gene where truncating variants are mechanism of disease), PM3 (PMID:18154657 reported a compound het AS patient also carrying V424I) = likely benign

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