Submissions for variant NM_001378454.1(ALMS1):c.3311G>A (p.Gly1104Asp)

gnomAD frequency: 0.00204  dbSNP: rs201074268

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001721324	SCV000529307	likely benign	not provided	2021-03-18	criteria provided, single submitter	clinical testing
Invitae	RCV000468687	SCV000554309	likely benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172515	SCV001335568	benign	Monogenic diabetes	2019-01-25	criteria provided, single submitter	research	ACMG criteria: BP4 (8 predictors + REVEL score 0.117), BS2 (1 homozygotes in gnomAD), BP1 (missense when truncating are cause of disease)= benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000419259	SCV001363027	benign	not specified	2022-02-06	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.3308G>A/p.Gly1103Asp (also known as c.3314G>A in RefSeq) results in a non-conservative amino acid change located in the Alstrom syndrome repeat (IPR040972) of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 248562 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although the variant has been reported in a paper describing the mutational spectrum of Alstrom syndrome, this publication provides no primary evidence supporting a pathogenic outcome (Marshall_2015). To our knowledge, no occurrence of c.3308G>A in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (TTR c.424G>A , p.Val1421Ile), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000419259	SCV002070953	likely benign	not specified	2021-12-26	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000468687	SCV002605254	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 rs201074268 in Alstrom syndrome yet.
Ambry Genetics	RCV002451018	SCV002611590	likely benign	Cardiovascular phenotype	2019-01-26	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.
CeGaT Center for Human Genetics Tuebingen	RCV001721324	SCV004154987	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ALMS1: BP4
Natera, Inc.	RCV000468687	SCV002080480	benign	Alstrom syndrome	2019-12-05	no assertion criteria provided	clinical testing