ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.2039A>G (p.Tyr680Cys) (rs199573929)

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Total submissions: 7
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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 2018-09-06 criteria provided, single submitter clinical testing The Y680C variant in the ALMS1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been reported in ClinVar as a variant of uncertain significance by several clinical laboratories (SCV000246357.1; SCV000342058.3; SCV000541338.3; Landrum et al., 2016). The Y680C variant is observed in 76/30,778 (0.25%) alleles from individuals of South Asian background in large population cohorts, though d no individuals were reported to be homozygous (Lek et al., 2016). The Y680C 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726112 SCV000342058 uncertain significance not provided 2016-06-07 criteria provided, single submitter clinical testing
Invitae RCV000726112 SCV000541338 likely benign not provided 2019-02-28 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, Partners HealthCare 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 , 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.
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; 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%).

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