ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1420C>A (p.His474Asn) (rs200454461)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000553360 SCV000631766 uncertain significance Alstrom syndrome 2019-06-11 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 475 of the ALMS1 protein (p.His475Asn). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and asparagine. This variant is present in population databases (rs200454461, ExAC 0.05%) but has not been reported in the literature in individuals with an ALMS1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "tolerated"; PolyPhen-2: "possibly_damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001293477 SCV001482055 uncertain significance not specified 2021-02-01 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.1420C>A (p.His474Asn) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249078 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (6e-05 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1420C>A in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Nilou-Genome Lab RCV000553360 SCV001716374 uncertain significance Alstrom syndrome 2021-05-18 criteria provided, single submitter clinical testing
GeneDx RCV001553245 SCV001774075 uncertain significance not provided 2020-01-14 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

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