ClinVar Genomic variation as it relates to human health

Reported in a patient with dilated cardiomyopathy in published literature (Burstein et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 210126; ClinVar); This variant is associated with the following publications: (PMID: 32746448)

p.Tyr680Cys in exon 8 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 0.25% (76/30778) South Asian and 0. 23% (293/125986) European chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs199573929). Tyrosine (Tyr) at positi on 680 is not highly conserved in mammals and evolutionary distant species, with one mammal (golden hamster) carrying a cystine (Cys) at this position, supporti ng that this change at this position may be tolerated. Additional computational computational prediction tools and conservation analysis suggest that this varia nt may not impact the protein. ACMG/AMP Criteria applied: BS1_P; BP4.

ACMG criteria: BP1, BS1 (0.2% MAF in gnomAD SA and ENF) [REVEL 0.191, PP3 (3), BP4 (6)= conflicting evidence, not using]= likely benign

Variant summary: ALMS1 c.2033A>G/p.Tyr678Cys (also known as c.2039A>G/p.Tyr680Cys) results in a non-conservative amino acid change located in the Alstrom syndrome repeat region (IPR040972) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 248830 control chromosomes, predominantly at a frequency of 0.0025 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2033A>G has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=5, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign.

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 rs199573929 in Alstrom syndrome yet.

The p.Tyr680Cys (also referred to as p.Tyr678Cys) variant in the ALMS1 gene has been previously reported in 2 unrelated individuals, 1 individual was heterozygous without a second variant identified, and 1 individual was compound heterozygous but had a phenotype inconsistent with Alstrom syndrome (Campbell et al., 2018; Celestino-Soper et al., 2015). This variant has also been identified in 76/30,598 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This allele frequency is greater than would be expected to be disease-causing for Alstrom syndrome. Previously reported disease-causing variants in ALMS1 have been primarily truncating variants, whereas this variant results in a single amino acid substitution. The significance of this type of variation in the ALMS1 gene is currently unclear. Computational tools predict that the p.Tyr680Cys variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Tyr680Cys variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BS1_supporting

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

Given its frequency in a large number of controls, no case data, and the autosomal recessive inheritance pattern of the associated disease, we consider this variant a variant of uncertain significance likely benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been seen in any cases of atrial fibrillation or ALMS1-related disease. Testing for our patient was performed at Invitae. 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. Our patient was only found to have one variant in this gene and does not have a phenotype consistent with this condition. This sequence change replaces tyrosine with cysteine at codon 680 of the ALMS1 protein (p.Tyr680Cys). The tyrosine residue is weakly conserved and there is a large physicochemical di erence between tyrosine and cysteine. Algorithms developed to predict the e ect of missense changes on protein structure and function do not agree on the potential impact of this missense change. The variant is present in 422 of 140,893 (MAF = 0.15%) total individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant is present in 292 of 63,046 European Non-Finnish individuals (MAF= 0.23%).