ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11641C>T (p.His3881Tyr)

gnomAD frequency: 0.00102  dbSNP: rs142278066
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Total submissions: 11
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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 likely benign not provided 2021-02-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18154657, 25846608, 28502102, 26082521, 28717663)
Laboratory for Molecular Medicine,Mass General Brigham 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000825113 SCV001467938 likely benign not specified 2022-05-11 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.11638C>T (p.His3880Tyr, also known as c.11644C>T in RefSeq) 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 0.00097 in 280780 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European subpopulation is equal to the estimated maximal expected allele frequency for a pathogenic variant in in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.11638C>T has been reported in the literature in individuals affected with Alstrom Syndrome and Bardet-Biedl syndrome (Joy_2007, Pereiro_2010, Ozanturk_2015, Castro-Sanchez_2015, Chen_2017). These reports do not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. In addition, co-occurrences with other pathogenic variants have been reported, one individual harbored BBS1 c.1169T>G (p.Met390Arg, homozygote, Castro-Sanchez_2015) and one individual carried BBS2 c.613-1G>C and BBS2 c.717+1G>A (Chen_2017), providing supporting evidence for a benign role. Functional studies report experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Alvarez-Satta_2017, Chen_2017). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab RCV000229716 SCV001653407 uncertain significance Alstrom syndrome 2021-05-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000825113 SCV002070961 uncertain significance not specified 2017-09-14 criteria provided, single submitter clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000413261 SCV001800079 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000825113 SCV001924584 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000825113 SCV001929171 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000413261 SCV001964134 likely benign not provided no assertion criteria provided clinical testing

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