ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1609C>G (p.Leu537Val) (rs202111717)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476920 SCV000541360 uncertain significance Alstrom syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 538 of the ALMS1 protein (p.Leu538Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs202111717, ExAC 0.04%). This variant has not been reported in the literature in individuals with a ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 403950). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000732324 SCV000582649 uncertain significance not provided 2021-12-06 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Eurofins NTD, LLC RCV000732324 SCV000860266 uncertain significance not provided 2018-04-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000476920 SCV000897041 uncertain significance Alstrom syndrome 2018-10-31 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001172510 SCV001335563 likely benign Monogenic diabetes 2018-01-12 criteria provided, single submitter research ACMG criteria: BP4 (6 predictors), BP1 (missense when truncating are causative)=likely benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001358710 SCV001554535 uncertain significance not specified 2021-03-25 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.1606C>G (p.Leu536Val) results in a 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 0.00034 in 280694 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00034 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1606C>G in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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