ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.2036A>G (p.Tyr679Cys)

gnomAD frequency: 0.00146  dbSNP: rs199573929
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000194030 SCV000246357 uncertain significance not specified 2015-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000726112 SCV000329060 uncertain significance not provided 2022-07-22 criteria provided, single submitter clinical testing 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)
Eurofins NTD LLC (GA) RCV000726112 SCV000342058 uncertain significance not provided 2016-06-07 criteria provided, single submitter clinical testing
Invitae RCV000463604 SCV000541338 likely benign Alstrom syndrome 2020-12-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000463604 SCV000897042 uncertain significance Alstrom syndrome 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000194030 SCV000967022 likely benign not specified 2018-04-17 criteria provided, single submitter clinical testing 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 ,; 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.
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001172511 SCV001335564 likely benign Monogenic diabetes 2018-06-29 criteria provided, single submitter research 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000194030 SCV001363026 likely benign not specified 2021-07-19 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.2033A>G (p.Tyr678Cys) 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 and 0.0024 within the South Asian and Non-Finnish European subpopulations, respectively, in the gnomAD database (exomes dataset). 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. c.2033A>G has been reported in the literature in heterozygous state in an individual with permanent pacemaker implantation from a study examining genes with involvement in cardiac pathogenicity (Celestino-Soper_2015). This report does 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. Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Likely benign (n=4) or VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab RCV000463604 SCV001653488 uncertain significance Alstrom syndrome 2021-05-18 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000726112 SCV000924735 uncertain significance not provided 2016-12-05 no assertion criteria provided provider interpretation 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;, 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%).
Natera, Inc. RCV000463604 SCV001453441 likely benign Alstrom syndrome 2020-01-13 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.