ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.9889A>G (p.Thr3297Ala) (rs58806616)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413135 SCV000491838 uncertain significance not specified 2016-11-21 criteria provided, single submitter 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.
Invitae RCV000461539 SCV000554297 benign Alstrom syndrome 2019-12-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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
Integrated Genetics/Laboratory Corporation of America 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, Partners HealthCare 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, http://exac.broadinstitute.org; dbSNP rs58806616).

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.