ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.8362A>G (p.Ile2788Val) (rs200075429)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000595220 SCV000705442 uncertain significance not provided 2017-02-15 criteria provided, single submitter clinical testing
Invitae RCV000794425 SCV000933830 uncertain significance Alstrom syndrome 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2788 of the ALMS1 protein (p.Ile2788Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200075429, ExAC 0.09%). This variant has been observed along with two other variants in the same ALMS1 gene in individuals with clinical features of ALMS1-related disease (PMID: 25468891, Invitae). This variant is also known as c.8356A>G, p.Ile2786Val in the literature. ClinVar contains an entry for this variant (Variation ID: 499776). 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.
Integrated Genetics/Laboratory Corporation of America RCV001175497 SCV001339095 uncertain significance not specified 2020-03-23 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.8356A>G (p.Ile2786Val) 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 5.7e-05 in 247260 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (5.7e-05 vs 0.0022), allowing no conclusion about variant significance. c.8356A>G has been reported in the literature in one individual affected with Usher syndrome type I (Bujakowska_2014). The report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no occurrence of c.8356A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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