ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1548C>G (p.Asp516Glu) (rs202002052)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443659 SCV000533085 uncertain significance not specified 2016-10-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The D517E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the D517E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and where Glutamic acid is the wild type in the kangaroo rat. In silico analysis suggests this variant likely does not alter the protein structure/function.
Invitae RCV000860715 SCV001000852 likely benign Alstrom syndrome 2020-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000443659 SCV001519472 uncertain significance not specified 2021-03-15 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.1548C>G (p.Asp516Glu), also known as c.1551C>G (p.Asp517Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 249080 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00011 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1548C>G in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have 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 classified the variant as likely benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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