ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1453A>G (p.Ile485Val)

gnomAD frequency: 0.00195  dbSNP: rs73945001
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724486 SCV000232743 uncertain significance not provided 2015-01-29 criteria provided, single submitter clinical testing
Invitae RCV001080812 SCV000290073 benign Alstrom syndrome 2022-11-04 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV000445450 SCV000536963 benign Monogenic diabetes 2019-02-08 criteria provided, single submitter research ACMG criteria: BP4 (8 predictors, REVEL 0.017), BP1(missense variant when mutations are truncating), BS2 (2 homozygotes in gnomAD Eur NF), BS1 (0.2% MAF in gnomAD latino, eurNF, other)=benign (Emory classified as VUS)
Genetic Services Laboratory, University of Chicago RCV000180331 SCV000593110 likely benign not specified 2021-04-15 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000724486 SCV001152348 likely benign not provided 2018-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000180331 SCV001467939 benign not specified 2020-12-07 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.1453A>G (p.Ile485Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 279644 control chromosomes in the gnomAD database, including 2 homozygotes. The variant was found predominantly within the Latino- (allele frequency: 0.0026) and the non-Finnish European (0.0023) subpopulations, and the observed variant frequency within these control individuals is approximately 1.3 to 1.4-fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome with Dilated Cardiomyopathy phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.1453A>G in individuals affected with Alstrom Syndrome with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x), likely benign (1x) or benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab RCV001080812 SCV001712294 benign Alstrom syndrome 2021-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV002390443 SCV002696702 likely benign Cardiovascular phenotype 2022-05-09 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV001080812 SCV003928149 uncertain significance Alstrom syndrome criteria provided, single submitter research Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs73945001 in Alstrom syndrome yet.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000724486 SCV000924730 uncertain significance not provided 2017-05-02 no assertion criteria provided provider interpretation Given this variant's presence in a large number of controls, no case data, the fact that Valine is the default amino acid in more than one species, and the autosomal recessive inheritance pattern of the disease with which ALMS1 is associated, we consider this variant a variant of uncertain significance, probably benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is no case data for this variant (and searched alternative notations p.Ile485Val) The ALMS1 gene is associated with autosomal RECESSIVE Alström syndrome. Alström syndrome includes cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated or restrictive cardiomyopathy, the insulin resistance syndrome, and multiple organ failure. Most Pathogenic variants in ALMS1 listed in ClinVar are truncating (frameshift or nonsense) and not missense like this one. According to ExAC, ALMS1 is tolerant of both synonymous (z= -2.46) and missense (z= -6.40) change, while it is intolerant to loss-of-function change (pLI= 0.00). This observation agrees with available case data: published cases of Alström syndrome are caused by a loss-of-function of both copies of the ALMS1 gene. This is a conservative amino acid change, resulting in the replacement of a nonpolar Isoleucine with a nonpolar Valine. Isoleucine at this location is poorly conserved across mammalian species. In fact, Valine is the default amino acid in at least two mammalian species, suggesting that this missense change does not adversely affect protein function. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). There are no Likely Pathogenic or Pathogenic variants listed within 10 amino acids of this residue in ClinVar as of 4/29/2017. This variant is present in ClinVar. It has been submitted by Emory Genetics Laboratory and Invitae. Both labs classify this variant as a variant of uncertain significance. The testing lab uses a different Ensembl transcript for this gene than that which directly corresponds to the HGVS transcript (ENST00000264448) according to publicly-available software. According to the ENST00000264448 transcript, this variant would be reported as p.Ile486Val. This variant (rs73945001) was reported in 456 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. (Because gnomAD uses a different transcript, it is listed as p.Ile485Val.) The overall MAF is 0.165%. In Latinos the MAF 0.25%, and in non-Finnish Europeans it is 0.23%. Our patient’s ancestry is from Portugal and Germany. The phenotype of the individuals in gnomAD is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.
Natera, Inc. RCV001080812 SCV001458905 benign Alstrom syndrome 2020-09-16 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000724486 SCV001800737 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000724486 SCV001920066 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000724486 SCV001931834 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000180331 SCV001968297 benign not specified no assertion criteria provided clinical testing

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