Submissions for variant NM_001378454.1(ALMS1):c.10751A>T (p.Gln3584Leu)

gnomAD frequency: 0.00310  dbSNP: rs144486524

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224455	SCV000281198	likely benign	not provided	2015-08-26	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Invitae	RCV001084997	SCV000290062	likely benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000224455	SCV000535048	benign	not provided	2020-05-18	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445421	SCV000536991	likely benign	Monogenic diabetes	2018-02-09	criteria provided, single submitter	research	ACMG criteria: BS2 (type2diabetesgenetics.org), BP4 (6 predictors), BP1 (most causal variants are truncating variants), Note:similar MAF in TODAY/1000G=likely benign
Genetic Services Laboratory, University of Chicago	RCV000436742	SCV000593115	likely benign	not specified	2017-02-07	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000436742	SCV000857952	benign	not specified	2017-11-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436742	SCV000864100	benign	not specified	2021-03-11	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.10748A>T (p.Gln3583Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 248684 control chromosomes, predominantly at a frequency of 0.0094 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 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.10748A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000436742	SCV000967144	likely benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing	p.Gln3583Leu in exon 16 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.87% (84/9696) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144486524).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001084997	SCV002605268	likely benign	Alstrom syndrome		criteria provided, single submitter	research	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs144486524 in Alstrom syndrome yet.
Ambry Genetics	RCV002417981	SCV002723773	likely benign	Cardiovascular phenotype	2019-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000224455	SCV004155006	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	ALMS1: BP4, BS2