ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.3311G>A (p.Gly1104Asp)

gnomAD frequency: 0.00204  dbSNP: rs201074268
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001721324 SCV000529307 likely benign not provided 2021-03-18 criteria provided, single submitter clinical testing
Invitae RCV000468687 SCV000554309 likely benign Alstrom syndrome 2021-12-18 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001172515 SCV001335568 benign Monogenic diabetes 2019-01-25 criteria provided, single submitter research ACMG criteria: BP4 (8 predictors + REVEL score 0.117), BS2 (1 homozygotes in gnomAD), BP1 (missense when truncating are cause of disease)= benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000419259 SCV001363027 benign not specified 2022-02-06 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.3308G>A/p.Gly1103Asp (also known as c.3314G>A in RefSeq) results in a non-conservative amino acid change located in the Alstrom syndrome repeat (IPR040972) of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 248562 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although the variant has been reported in a paper describing the mutational spectrum of Alstrom syndrome, this publication provides no primary evidence supporting a pathogenic outcome (Marshall_2015). To our knowledge, no occurrence of c.3308G>A in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (TTR c.424G>A , p.Val1421Ile), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory,University of Chicago RCV000419259 SCV002070953 likely benign not specified 2021-12-26 criteria provided, single submitter clinical testing
Natera, Inc. RCV000468687 SCV002080480 benign Alstrom syndrome 2019-12-05 no assertion criteria provided clinical testing

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