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

gnomAD frequency: 0.00042  dbSNP: rs200529564

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000526065	SCV000631781	uncertain significance	Alstrom syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1409 of the ALMS1 protein (p.Val1409Ile). This variant is present in population databases (rs200529564, gnomAD 0.06%). This missense change has been observed in individual(s) with Alstrom syndrome (PMID: 28432734). 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: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002330845	SCV002629645	likely benign	Cardiovascular phenotype	2022-03-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.