ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.9715C>T (p.Arg3239Cys) (rs201252375)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082321 SCV000541330 likely benign Alstrom syndrome 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000520369 SCV000618206 uncertain significance not provided 2017-11-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The R3239C variant has not been published as pathogenic or been reported as benign to our knowledge. The R3239C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position not conserved across species, and the majority (2 out of 3) of in silico analyses predict this variant likely does not alter the protein structure/function. Additionally, R3239C was observed in 74/10,150 (0.7%) alleles from individuals of Ashkenazi Jewish background from large population cohorts (Lek et al., 2016). Lastly, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date introduce a premature termination codon (Marshall et al., 2012; Stenson et al., 2014).
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000520369 SCV000924728 uncertain significance not provided 2017-05-02 no assertion criteria provided provider interpretation p.Arg3239Cys (c.9715C>T) in exon 11 of the ALMS1 gene (NM_015120.4) Chromosome position: 2:73747074 C / T Based on the information reviewed below, including this variant’s relatively high frequency in the Ashkenazi Jewish population (MAF=0.73%), coupled with poor conservation at this residue across evolution (several species have Cysteine as the default amino acid), we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. The ALMS1 gene is associated with autosomal recessive Alstrom syndrome (MedGen UID: 78675). For this reason, any one heterozygous variant is an unlikely explanation for disease, although it cannot be ruled out. This variant has not been reported in the literature in association with disease. It has been reported to ClinVar only by Invitae as of 4/29/2017. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine that it capable of forming disulfide bridges. Arginine at this location is very poorly conserved across vertebrate species. In fact, Cysteine is the default amino acid in at least 3 species. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; 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. Most Pathogenic variants in ALMS1 listed in ClinVar are truncating (frameshift or nonsense) and not missense like this one. This particular transcript for ALMS1 is not found in gnomAD. However, there is an Arg3237Cys variant in gnomAD (rs201252375) that appears to be the same thing. It has been reported in 170 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.06%. Specifically, the variant was observed in 74/5,075 Ashkenazi Jews (for the highest allele frequency: 0.73%), 81/63,302 non-Finnish Europeans, 6 Finnish Europeans, 6 Other, 2 Latinos, and 1 South Asian. Our patient’s ancestry is from Belarus and Ukraine. 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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