Submissions for variant NM_001378454.1(ALMS1):c.11821G>A (p.Gly3941Ser)

gnomAD frequency: 0.00422  dbSNP: rs61741524

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175336	SCV000226807	benign	not specified	2014-08-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001697125	SCV000533002	benign	not provided	2018-06-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475832	SCV000554290	benign	Alstrom syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000175336	SCV000711945	benign	not specified	2017-12-21	criteria provided, single submitter	clinical testing	p.Gly3940Ser in exon 18 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 1.30% (309/24020) of African chro mosomes including 4 homozygotes by the Genome Aggregation Database (gnomAD, http ://gnomAD.broadinstitute.org; dbSNP rs61741524). ACMG/AMP criteria applied: BA1 .
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000175336	SCV000864123	benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.11818G>A (p.Gly3940Ser, alternative name c.11824G>A) 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 0.0014 in 277116 control chromosomes, predominantly within the African subpopulation at a frequency of 0.013 in the gnomAD database, including 4 homozygotes. The observed variant frequency within African control individuals is approximately 5.8 fold above 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 origin. c.11818G>A has been reported in the literature in patients with clinical features of Alstrom syndrome. But this report does not provide unequivocal conclusions about association of the variant with cardiomyopathy or with Alstrom syndrome and is listed among a series of SNV's that were deemed as being unlikely to be pathogenic by the authors. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as Benign.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172501	SCV001335554	benign	Monogenic diabetes	2019-02-15	criteria provided, single submitter	research	ACMG criteria: BP4 (9 predictors, Revel score 0.031), BA1 (1.3% in gnomAD African) , BP1, BS2 (4 homozygotes in gnomAD African)= benign
Genetic Services Laboratory, University of Chicago	RCV000175336	SCV002070962	benign	not specified	2021-11-16	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000475832	SCV002605269	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 rs61741524 in Alstrom syndrome yet.
Ambry Genetics	RCV002336424	SCV002640317	benign	Cardiovascular phenotype	2019-01-26	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000475832	SCV004564097	benign	Alstrom syndrome	2023-09-20	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001697125	SCV005240753	benign	not provided		criteria provided, single submitter	not provided
Clinical Genetics, Academic Medical Center	RCV000175336	SCV001923634	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000175336	SCV001927901	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001697125	SCV001969622	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001697125	SCV002035947	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000475832	SCV002079037	benign	Alstrom syndrome	2019-12-09	no assertion criteria provided	clinical testing