ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.9886A>G (p.Thr3296Ala)

gnomAD frequency: 0.00296  dbSNP: rs58806616
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461539 SCV000554297 benign Alstrom syndrome 2024-01-31 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000413135 SCV000708536 benign not specified 2017-05-15 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV001172529 SCV001335582 benign Monogenic diabetes 2018-03-16 criteria provided, single submitter research ACMG criteria: PP3 (6 predictors), BP4 (3 predictors), BS1 (1.13% in 1000G African population and disease frequency is 1 in 10,000), BS2 (4 homozygotes in gnomAD)=benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000413135 SCV001363237 benign not specified 2019-07-15 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.9883A>G (p.Thr3295Ala, also known as c.9889A>G) results in a non-conservative amino acid change in 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 0.00063 in 249334 control chromosomes, predominantly at a frequency of 0.0098 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4.4 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 African or African-American origin. To our knowledge, no occurrence of c.9883A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, two classified it as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000413135 SCV001365658 likely benign not specified 2016-03-21 criteria provided, single submitter clinical testing p.Thr3295Ala in exon 12 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.93% (91/9788) of African chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs58806616).
GeneDx RCV001692093 SCV001912356 benign not provided 2019-05-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV002379270 SCV002693243 likely benign Cardiovascular phenotype 2019-06-06 criteria provided, single submitter clinical testing 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV000461539 SCV003928175 uncertain risk allele Alstrom syndrome criteria provided, single submitter research 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 rs58806616 in Alstrom syndrome yet.
GeneDx RCV000413135 SCV000491838 uncertain significance not specified 2016-11-21 flagged submission clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The T3297A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T3297A 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. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, the Exome Aggregation Consortium (ExAC) reports T3297A was observed in 91/9,788 (0.9%) alleles from individuals of African background, including one homozygous individual, indicating it may be a rare benign variant in this population. Lastly, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date are predicted to cause premature protein truncation (Marshall et al., 2012; Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Natera, Inc. RCV000461539 SCV001459595 benign Alstrom syndrome 2020-01-01 no assertion criteria provided clinical testing

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