Submissions for variant NM_001378454.1(ALMS1):c.5189A>G (p.Glu1730Gly)

gnomAD frequency: 0.00065  dbSNP: rs201390755

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080878	SCV000290091	likely benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731324	SCV000859128	uncertain significance	not provided	2018-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000731324	SCV001152351	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ALMS1: BP4
Genome-Nilou Lab	RCV001080878	SCV001716340	likely benign	Alstrom syndrome	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000731324	SCV001788361	likely benign	not provided	2020-06-01	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001701794	SCV002572416	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.5186A>G/p.Glu1729Gly (also known as c.5192A>G in RefSeq) 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 0.00085 in 249014 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00085 vs 0.0018), allowing no conclusion about variant significance. c.5186A>G has been reported in two heterozygous individuals with clinical features of Alstrom Syndrome without strong evidence for causality (Marshall_2015). This report does not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25846608, 26283575). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely benign (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002338755	SCV002641500	likely benign	Cardiovascular phenotype	2021-06-10	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.
New York Genome Center	RCV001080878	SCV003925068	uncertain significance	Alstrom syndrome	2022-04-06	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000731324	SCV001799748	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701794	SCV001927157	benign	not specified		no assertion criteria provided	clinical testing