Submissions for variant NM_001378454.1(ALMS1):c.11641C>T (p.His3881Tyr)

gnomAD frequency: 0.00102  dbSNP: rs142278066

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229716	SCV000290068	uncertain significance	Alstrom syndrome	2022-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 3882 of the ALMS1 protein (p.His3882Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs142278066, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with an ALMS1-related disease. However, in one of these individuals the variant was found to co-occur with 2 pathogenic variants in the BBS2 gene. (PMID: 18154657, 28502102). ClinVar contains an entry for this variant (Variation ID: 240979). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000413261	SCV000491552	likely benign	not provided	2021-02-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18154657, 25846608, 28502102, 26082521, 28717663)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825113	SCV000966368	likely benign	not specified	2018-10-04	criteria provided, single submitter	clinical testing	The p.His3880Tyr variant is classifed as likely benign because it has been ident ified in 0.17% (218/126250) of European chromosomes by gnomAD (http://gnomad.bro adinstitute.org), and computational prediction tools and conservation analysis s uggest that this variant may not impact the protein. Furthermore, although this variant has been reported in two individuals with features of Alstrom syndrome, both individuals harbored pathogenic variants in BBS1 and BBS2 indicating a diag nosis of Bardet-Biedl syndrome (Joy 2007, Chen 2017, Alvarez-Satta 2017). In vi tro functional studies performed in patient fibroblast cells indicate that the v ariant did not have an effect on the protein function (Chen 2017, Alvarez-Satta 2017). This variant is reported in ClinVar (Variation ID: 240979). In summary, t his variant meets criteria to be classified as likely benign. ACMG/AMP Criteria applied: BS1_Supporting, BP4, BP5, BS3_Supporting.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172499	SCV001335552	likely benign	Monogenic diabetes	2019-02-15	criteria provided, single submitter	research	ACMG criteria: BP4 (REVEL 0.042 + 5 predictors), BP1 (missense in gene where truncating variants are mechanism of disease), PM3 (PMID:18154657 reported a compound het AS patient also carrying V424I) = likely benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825113	SCV001467938	likely benign	not specified	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.11638C>T (p.His3880Tyr, also known as c.11644C>T in RefSeq) 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 0.00097 in 280780 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European subpopulation is equal to the estimated maximal expected allele frequency for a pathogenic variant in in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.11638C>T has been reported in the literature in individuals affected with Alstrom Syndrome and Bardet-Biedl syndrome (Joy_2007, Pereiro_2010, Ozanturk_2015, Castro-Sanchez_2015, Chen_2017). These reports do not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. In addition, co-occurrences with other pathogenic variants have been reported, one individual harbored BBS1 c.1169T>G (p.Met390Arg, homozygote, Castro-Sanchez_2015) and one individual carried BBS2 c.613-1G>C and BBS2 c.717+1G>A (Chen_2017), providing supporting evidence for a benign role. Functional studies report experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Alvarez-Satta_2017, Chen_2017). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV000229716	SCV001653407	uncertain significance	Alstrom syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000825113	SCV002070961	uncertain significance	not specified	2017-09-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321884	SCV002628947	likely benign	Cardiovascular phenotype	2021-08-25	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	RCV000413261	SCV004155012	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ALMS1: BP4
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000413261	SCV001800079	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000825113	SCV001924584	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000825113	SCV001929171	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000413261	SCV001964134	likely benign	not provided		no assertion criteria provided	clinical testing