ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.4988C>T (p.Thr1663Ile)

gnomAD frequency: 0.00267  dbSNP: rs188807564
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227881 SCV000290090 likely benign Alstrom syndrome 2021-12-17 criteria provided, single submitter clinical testing
GeneDx RCV001705277 SCV000532852 benign not provided 2019-08-14 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV000445498 SCV000536972 likely benign Monogenic diabetes 2017-11-10 criteria provided, single submitter research ACMG criteria: BP4 (9 predictors), BS2 (33 cases and 12 controls in and one homozygous in ExAC), BP1 (missense in gene with truncating cause disease)=likely benign
Genetic Services Laboratory,University of Chicago RCV000433447 SCV000593111 likely benign not specified 2016-03-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000433447 SCV000711944 likely benign not specified 2016-03-21 criteria provided, single submitter clinical testing p.Thr1662Ile in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 0.86% (83/9656) of African chromos omes by the Exome Aggregation Consortium (ExAC,; dbSNP rs188807564).
Eurofins NTD LLC (GA) RCV000433447 SCV000862397 likely benign not specified 2018-07-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000433447 SCV000864092 uncertain significance not specified 2018-05-29 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.4985C>T (p.Thr1662Ile, alternative name c.4991C>T) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 276668 control chromosomes, predominantly at a frequency of 0.008 within the African subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.4985C>T, has not been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign x4, VUS x1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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