ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.6302C>G (p.Ser2101Trp) (rs28730854)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001698278 SCV000531745 likely benign not provided 2020-08-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25846608)
Invitae RCV000865671 SCV001006674 likely benign Alstrom syndrome 2020-11-22 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001172506 SCV001335559 benign Monogenic diabetes 2017-10-06 criteria provided, single submitter research ACMG criteria: BP4 (4 predictors), PP3 (2 predictors), BS1 (4.97% in European in 1000g), BS2 (61 homozygotes in ExAC), BP1 (missense in gene with truncating known) = benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000439863 SCV001339093 uncertain significance not specified 2020-03-16 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.6299C>G (p.Ser2100Trp; also known as legacy name c. 6305C>G; p.Ser2102Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 247674 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00029 vs 0.0022), allowing no conclusion about variant significance. c.6299C>G has been reported in the literature in at least one individual affected with Alstrom Syndrome (Marshall_2015). This report does 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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