ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.6082T>C (p.Ser2028Pro) (rs149096794)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001580495 SCV000535171 likely benign not provided 2021-08-05 criteria provided, single submitter clinical testing
Invitae RCV000468666 SCV000554292 likely benign Alstrom syndrome 2020-12-08 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001172526 SCV001335579 likely benign Monogenic diabetes 2017-02-17 criteria provided, single submitter research ACMG criteria: PP3 (3 predictors), BS1 (1% in 1000G-AFR), BP4 (4 predictors), BP1 (truncating known to cause disease), (BS2)for 1 homozygote in ExAC=Likely Benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000436669 SCV001363240 benign not specified 2019-09-23 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.6079T>C, also referred to as c.6085T>C using the refseq HGVS naming convention (p.Ser2027Pro), results in a non-conservative amino acid change located in the Alstrom syndrome repeat domain (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 0.00039 in 249198 control chromosomes, predominantly at a frequency of 0.0055 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.5 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.6079T>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

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