ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.6305C>G (p.Ser2102Trp) (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 RCV000439863 SCV000531745 uncertain significance not specified 2017-05-19 criteria provided, single submitter clinical testing The S2102W variant in the ALMS1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 5900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S2102W 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. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S2102W as a variant of uncertain significance.
Invitae RCV000865671 SCV001006674 likely benign Alstrom syndrome 2019-12-31 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
Integrated Genetics/Laboratory Corporation of America 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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