ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.4222G>A (p.Val1408Ile)

gnomAD frequency: 0.00022  dbSNP: rs200529564
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526065 SCV000631781 uncertain significance Alstrom syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1409 of the ALMS1 protein (p.Val1409Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs200529564, ExAC 0.08%). This variant has been observed as homozygous in an individual with Alstrom syndrome (PMID: 28432734). However, in that individual a homozygous pathogenic allele was also identified in ALMS1, which suggests that this c.4225G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 459867). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001172518 SCV001335571 likely benign Monogenic diabetes 2017-03-03 criteria provided, single submitter research ACMG criteria: BP4 (6 predictors), BP1 (missense when truncating cause disease)=likely benign
Baylor Genetics RCV000526065 SCV001528929 uncertain significance Alstrom syndrome 2018-04-26 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375572 SCV001572460 likely benign not specified 2021-06-21 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.4219G>A (p.Val1407Ile) (RefSeq c.4225G>A, p.Val1409Ile) 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 (ACMG BP4). The variant allele was found at a frequency of 0.00041 in 249300 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00041 vs 0.0018), allowing no conclusion about variant significance. c.4219G>A has been reported in the literature in cis with another pathogenic variant (c.5081del, p.Pro1692Leufs*39) in two individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy (Astuti_2017)(ACMG BP2). Considering this finding, the authors reported a classification of this variant as likely benign. These report(s) do not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2, likely benign, n=1). At-least one submitter cites overlapping evidence utilized in the context of this evaluation and reports a likely benign outcome. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV001565361 SCV001788695 uncertain significance not provided 2021-12-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28432734)
Genetic Services Laboratory,University of Chicago RCV001375572 SCV002067593 uncertain significance not specified 2021-06-21 criteria provided, single submitter clinical testing DNA sequence analysis of the ALMS1 gene demonstrated a sequence change, c.4225G>A, in exon 8 that results in an amino acid change, p.Val1409Ile. This sequence change has been described in gnomAD with a frequency of 0.059% in the Non-Finnish European sub-population (dbSNP rs200529564). The p.Val1409Ile change affects a moderately conserved amino acid residue located in a domain of the ALMS1 protein that is not known to be functional. The p.Val1409Ile substitution appears to be tolerated using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The c.4225G>A sequence change has been reported in the homozygous state in two affected individuals from the same family. However, both individuals were also homozygous for a likely pathogenic variant (c.5081del, p.Pro1692Leufs*39) (PMID: 28432734). Due to the lack of sufficient evidences, the clinical significance of the p.Val1409Ile change remains unknown at this time.

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