Submissions for variant NM_001378454.1(ALMS1):c.1453A>G (p.Ile485Val)

gnomAD frequency: 0.00195  dbSNP: rs73945001

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724486	SCV000232743	uncertain significance	not provided	2015-01-29	criteria provided, single submitter	clinical testing
Invitae	RCV001080812	SCV000290073	benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445450	SCV000536963	benign	Monogenic diabetes	2019-02-08	criteria provided, single submitter	research	ACMG criteria: BP4 (8 predictors, REVEL 0.017), BP1(missense variant when mutations are truncating), BS2 (2 homozygotes in gnomAD Eur NF), BS1 (0.2% MAF in gnomAD latino, eurNF, other)=benign (Emory classified as VUS)
Genetic Services Laboratory, University of Chicago	RCV000180331	SCV000593110	likely benign	not specified	2021-04-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724486	SCV001152348	likely benign	not provided	2018-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180331	SCV001467939	benign	not specified	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.1453A>G (p.Ile485Val) results in a 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 0.0017 in 279644 control chromosomes in the gnomAD database, including 2 homozygotes. The variant was found predominantly within the Latino- (allele frequency: 0.0026) and the non-Finnish European (0.0023) subpopulations, and the observed variant frequency within these control individuals is approximately 1.3 to 1.4-fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome with Dilated Cardiomyopathy phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.1453A>G in individuals affected with Alstrom Syndrome with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x), likely benign (1x) or benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001080812	SCV001712294	benign	Alstrom syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390443	SCV002696702	likely benign	Cardiovascular phenotype	2022-05-09	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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001080812	SCV003928149	uncertain significance	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 rs73945001 in Alstrom syndrome yet.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000724486	SCV000924730	uncertain significance	not provided	2017-05-02	no assertion criteria provided	provider interpretation	Given this variant's presence in a large number of controls, no case data, the fact that Valine is the default amino acid in more than one species, and the autosomal recessive inheritance pattern of the disease with which ALMS1 is associated, we consider this variant a variant of uncertain significance, probably benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is no case data for this variant (and searched alternative notations p.Ile485Val) The ALMS1 gene is associated with autosomal RECESSIVE Alström syndrome. Alström syndrome includes cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated or restrictive cardiomyopathy, the insulin resistance syndrome, and multiple organ failure. Most Pathogenic variants in ALMS1 listed in ClinVar are truncating (frameshift or nonsense) and not missense like this one. According to ExAC, ALMS1 is tolerant of both synonymous (z= -2.46) and missense (z= -6.40) change, while it is intolerant to loss-of-function change (pLI= 0.00). This observation agrees with available case data: published cases of Alström syndrome are caused by a loss-of-function of both copies of the ALMS1 gene. This is a conservative amino acid change, resulting in the replacement of a nonpolar Isoleucine with a nonpolar Valine. Isoleucine at this location is poorly conserved across mammalian species. In fact, Valine is the default amino acid in at least two mammalian species, suggesting that this missense change does not adversely affect protein function. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). There are no Likely Pathogenic or Pathogenic variants listed within 10 amino acids of this residue in ClinVar as of 4/29/2017. This variant is present in ClinVar. It has been submitted by Emory Genetics Laboratory and Invitae. Both labs classify this variant as a variant of uncertain significance. The testing lab uses a different Ensembl transcript for this gene than that which directly corresponds to the HGVS transcript (ENST00000264448) according to publicly-available software. According to the ENST00000264448 transcript, this variant would be reported as p.Ile486Val. This variant (rs73945001) was reported in 456 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. (Because gnomAD uses a different transcript, it is listed as p.Ile485Val.) The overall MAF is 0.165%. In Latinos the MAF 0.25%, and in non-Finnish Europeans it is 0.23%. Our patient’s ancestry is from Portugal and Germany. The phenotype of the individuals in gnomAD is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.
Natera, Inc.	RCV001080812	SCV001458905	benign	Alstrom syndrome	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000724486	SCV001800737	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000724486	SCV001920066	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000724486	SCV001931834	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000180331	SCV001968297	benign	not specified		no assertion criteria provided	clinical testing