ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.1456A>G (p.Ile486Val) (rs73945001)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724486 SCV000232743 uncertain significance not provided 2015-01-29 criteria provided, single submitter clinical testing
Invitae RCV001080812 SCV000290073 benign Alstrom syndrome 2019-12-31 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 uncertain significance not specified 2017-01-09 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000724486 SCV001152348 likely benign not provided 2018-12-01 criteria provided, single submitter clinical testing
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.

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