Submissions for variant NM_001378454.1(ALMS1):c.9733G>A (p.Ala3245Thr)

gnomAD frequency: 0.00005  dbSNP: rs200432874

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175498	SCV001339096	uncertain significance	not specified	2020-03-02	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.9730G>A (p.Ala3244Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 249478 control chromosomes, predominantly at a frequency of 0.0018 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00015 vs 0.0022), allowing no conclusion about variant significance. c.9730G>A has been reported in the literature in individuals of East Asian ethnicity affected with retinitis pigmentosa without strong evidence for causality (e.g. Katagiri_2014, Xu_2015,2016). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001828590	SCV003495319	uncertain significance	Alstrom syndrome	2022-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3246 of the ALMS1 protein (p.Ala3246Thr). This variant is present in population databases (rs200432874, gnomAD 0.2%). 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: 918121). 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	RCV004590113	SCV005078976	uncertain significance	not provided	2024-05-03	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV004629476	SCV005127395	benign	Cardiovascular phenotype	2024-05-30	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Natera, Inc.	RCV001828590	SCV002078951	uncertain significance	Alstrom syndrome	2021-07-22	no assertion criteria provided	clinical testing