Submissions for variant NM_001378454.1(ALMS1):c.8411G>A (p.Arg2804His)

gnomAD frequency: 0.00057  dbSNP: rs201252809

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000514773	SCV000536368	likely benign	not provided	2020-11-16	criteria provided, single submitter	clinical testing
Invitae	RCV000468894	SCV000541333	likely benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514773	SCV000610094	uncertain significance	not provided	2017-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000468894	SCV000897045	uncertain significance	Alstrom syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000468894	SCV001781463	uncertain significance	Alstrom syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446761	SCV002678338	likely benign	Cardiovascular phenotype	2019-09-25	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114574	SCV003801102	uncertain significance	not specified	2023-11-14	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.8408G>A (p.Arg2803His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 248568 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00049 vs 0.0018), allowing no conclusion about variant significance. c.8408G>A has been reported in the literature in at least one individual affected with Alstrom Syndrome. This report does not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. 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: 25846608). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign n=3, VUS n=6). Based on the evidence outlined above, the variant was classified as uncertain significance.
New York Genome Center	RCV000468894	SCV003925078	uncertain significance	Alstrom syndrome	2021-10-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514773	SCV004154996	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	ALMS1: PM2, BP4
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000514773	SCV000924727	uncertain significance	not provided	2016-08-16	no assertion criteria provided	provider interpretation
Natera, Inc.	RCV000468894	SCV001453027	uncertain significance	Alstrom syndrome	2020-09-16	no assertion criteria provided	clinical testing