Submissions for variant NM_001378454.1(ALMS1):c.10774A>G (p.Thr3592Ala)

gnomAD frequency: 0.00051  dbSNP: rs200467041

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000524071	SCV000618291	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000803220	SCV000943082	uncertain significance	Alstrom syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 3593 of the ALMS1 protein (p.Thr3593Ala). This variant is present in population databases (rs200467041, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449854). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255513	SCV001431950	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.10771A>G (p.Thr3591Ala) 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 0.00011 in 248704 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. This frequency is only slight lower than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome (0.0012 vs 0.0014), suggesting this variant may not associate with the disease. To our knowledge, no occurrence of c.10771A>G in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.1505G>A, p.Arg502Gln; TTN c.62134C>T, p.Gln20712X; MYBPC3 c.927-9G>A; internal testing), providing supporting evidence for a benign role. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely benign (n=2) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002420308	SCV002728232	likely benign	Cardiovascular phenotype	2021-10-25	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.
Fulgent Genetics, Fulgent Genetics	RCV000803220	SCV002796925	uncertain significance	Alstrom syndrome	2022-03-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000803220	SCV001459598	likely benign	Alstrom syndrome	2019-10-28	no assertion criteria provided	clinical testing