Submissions for variant NM_001378454.1(ALMS1):c.2658A>G (p.Lys886=)

gnomAD frequency: 0.00262  dbSNP: rs80133984

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000228750	SCV000290079	benign	Alstrom syndrome	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001705276	SCV000531701	likely benign	not provided	2021-03-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000430379	SCV000864087	benign	not specified	2018-07-30	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.2655A>G (alternative c.2661A>G) alters a non-conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 0.00081 in 276666 control chromosomes, and was predominantly within the African subpopulation in the gnomAD database at a frequency of 0.0084, including 2 homozygotes. The observed variant frequency within African control individuals is approximately 3.8-fold above 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 origin. To our knowledge, no occurrence of c.2655A>G 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, and both classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002429128	SCV002743494	likely benign	Cardiovascular phenotype	2019-03-19	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705276	SCV001977856	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001705276	SCV001979210	likely benign	not provided		no assertion criteria provided	clinical testing