Submissions for variant NM_001378454.1(ALMS1):c.6553C>T (p.Pro2185Ser)

gnomAD frequency: 0.01077  dbSNP: rs77555300

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226842	SCV000290101	benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000429253	SCV000524250	benign	not specified	2016-12-05	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.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445433	SCV000536980	benign	Monogenic diabetes	2019-02-15	criteria provided, single submitter	research	ACMG criteria: BP1 (missense when truncating are ds causing), BA1 (3.4% MAF in gnomAD Africans), BS2 (18 homozygotes in gnomAD), BP4 (REVEL 0.028 + 8 predictors)= Benign (ALMS1 p.P2184S and p.K1810N are likely in LD)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000429253	SCV000711812	benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing	p.Pro2184Ser in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 3.31% (323/9752) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs77555300).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000429253	SCV000864116	likely benign	not specified	2016-02-15	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.6550C>T (alternative name c.6556C>T) variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to Ser. 4/5 in-silico tools predict this variant to be benign, but these in silico predictions have not been confirmed with functional studies. This variant is found in 355/120368 control chromosomes (6 homozygotes) at a frequency of 0.0029493, with the highest frequency in Africans (0.03312; 5 homozygotes). This African allele frequency significantly exceeds maximal expected frequency of a pathogenic allele (0.0022361), suggesting that this is a benign polymorphism in Africans. Mutations in the ALMS1 gene have been reported with autosomal recessive Alstrom disease (AS), which has estimated prevalence of 1/600,000. 60% of patients with Alstrom syndrome have Dilated Cardiomyopathy (DCM) among other presenting features such as obesity, retinal rod cone dystrophy, diabetes, and progressive hearing loss. This gene was included in Cardio Gene Screening panel based upon the reported findings of DCM in patients with AS. Mutations in ALMS1 gene have not been implicated in isolated cases of cardiomyopathy, which has higher prevalence (1/500), than the AS alone. Taken together, this is probably a normal variant and was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000226842	SCV002506091	benign	Alstrom syndrome	2022-02-08	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000226842	SCV002605261	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 rs77555300 in Alstrom syndrome yet.
Ambry Genetics	RCV002365209	SCV002665867	benign	Cardiovascular phenotype	2019-01-07	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000429253	SCV002034120	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001795372	SCV002035931	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000226842	SCV002082833	benign	Alstrom syndrome	2019-12-02	no assertion criteria provided	clinical testing