Submissions for variant NM_001378454.1(ALMS1):c.9914A>G (p.Asn3305Ser)

gnomAD frequency: 0.00158  dbSNP: rs142022233

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445528	SCV000536987	benign	Monogenic diabetes	2018-05-18	criteria provided, single submitter	research	ACMG criteria: [BP4 (3 predictors) PP3 (6 predictors) Revel score 0.193: conflicting data, not using], BS2 (20 homozygotes in gnomAD, all but 1 South Asian), BS1 (2.67% in South Asians in gnomAD), BP1 (missense variant when truncating is disease causing) (Partners/Invitae/GeneDx all call benign but no longer using BP6)= benign
Invitae	RCV000532855	SCV000631813	benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000602571	SCV000711823	benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing	p.Asn3304Ser in exon 13 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 2.76% (455/16484) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs142022233).
GeneDx	RCV000602571	SCV000714608	benign	not specified	2017-01-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000602571	SCV000864096	benign	not specified	2018-01-02	criteria provided, single submitter	clinical testing	Variant summary: The ALMS1 c.9911A>G (p.Asn3304Ser; alternative nomenclature c.9917A>G, p.N3306S) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant. This variant was found in 1363/276886 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.026704 (821/30744), including 19 homozygotes. This frequency is about 12 times the estimated maximal expected allele frequency of a pathogenic ALMS1 variant (0.0022361), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. An internal specimen also carries a pathogenic MYBPC3, supporting the benign role of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Ambry Genetics	RCV002379401	SCV002691015	benign	Cardiovascular phenotype	2019-05-30	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
CeGaT Center for Human Genetics Tuebingen	RCV003884537	SCV004699314	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ALMS1: BP4, BS1, BS2
Natera, Inc.	RCV000532855	SCV001453039	benign	Alstrom syndrome	2020-09-16	no assertion criteria provided	clinical testing