Submissions for variant NM_001378454.1(ALMS1):c.4988C>T (p.Thr1663Ile)

gnomAD frequency: 0.00267  dbSNP: rs188807564

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227881	SCV000290090	likely benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001705277	SCV000532852	benign	not provided	2019-08-14	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445498	SCV000536972	likely benign	Monogenic diabetes	2017-11-10	criteria provided, single submitter	research	ACMG criteria: BP4 (9 predictors), BS2 (33 cases and 12 controls in type2diabetesgenetics.org and one homozygous in ExAC), BP1 (missense in gene with truncating cause disease)=likely benign
Genetic Services Laboratory, University of Chicago	RCV000433447	SCV000593111	likely benign	not specified	2016-03-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000433447	SCV000711944	likely benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing	p.Thr1662Ile in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 0.86% (83/9656) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs188807564).
Eurofins Ntd Llc (ga)	RCV000433447	SCV000862397	likely benign	not specified	2018-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000433447	SCV000864092	likely benign	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.4985C>T/p.Thr1662Ile (also known as c.4991C>T in RefSeq) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 249086 control chromosomes, predominantly at a frequency of 0.0087 within the African or African-American subpopulation in the gnomAD database, including 3 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. c.4985C>T has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23033341). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002338754	SCV002640438	likely benign	Cardiovascular phenotype	2018-12-29	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 Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000227881	SCV003928170	uncertain significance	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 rs188807564 in Alstrom syndrome yet.
CeGaT Center for Human Genetics Tuebingen	RCV001705277	SCV004154991	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	ALMS1: BP4, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000227881	SCV004564345	likely benign	Alstrom syndrome	2023-01-03	criteria provided, single submitter	clinical testing