Submissions for variant NM_001378454.1(ALMS1):c.9822C>G (p.Thr3274=)

gnomAD frequency: 0.00245  dbSNP: rs201446579

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000415799	SCV000493281	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ALMS1: BP4, BP7
GeneDx	RCV000415799	SCV000531880	likely benign	not provided	2020-11-11	criteria provided, single submitter	clinical testing
Invitae	RCV001084056	SCV000631812	benign	Alstrom syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000443000	SCV001363236	benign	not specified	2019-04-22	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.9819C>G (also known as c.9825C>G) alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 249364 control chromosomes, predominantly at a frequency of 0.0029 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 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 Non-Finnish European origin. To our knowledge, no occurrence of c.9819C>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 (2x Benign/likely benign ; 1x uncertain significance). Based on the evidence outlined above, the variant was classified as benign.
Pars Genome Lab	RCV001084056	SCV001652886	likely benign	Alstrom syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002374623	SCV002689243	likely benign	Cardiovascular phenotype	2019-01-30	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 Genetics, Academic Medical Center	RCV000443000	SCV001917533	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000415799	SCV001974156	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000415799	SCV002034150	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001084056	SCV002078955	likely benign	Alstrom syndrome	2019-10-22	no assertion criteria provided	clinical testing