Submissions for variant NM_001378454.1(ALMS1):c.2065A>G (p.Thr689Ala)

gnomAD frequency: 0.00039  dbSNP: rs201804994

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234517	SCV000290075	uncertain significance	Alstrom syndrome	2022-10-18	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 690 of the ALMS1 protein (p.Thr690Ala). This variant is present in population databases (rs201804994, gnomAD 0.05%). 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: 240985). 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	RCV001723822	SCV000532509	uncertain significance	not provided	2024-06-17	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	RCV002418023	SCV002725651	likely benign	Cardiovascular phenotype	2021-04-21	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.
Fulgent Genetics, Fulgent Genetics	RCV000234517	SCV002794039	uncertain significance	Alstrom syndrome	2022-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782322	SCV005394526	uncertain significance	not specified	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.2062A>G (p.Thr688Ala), alternate nomenclature p.Thr689Ala/p.Thr690Ala, results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 248908 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome (0.00026 vs 0.0014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2062A>G in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 240985). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000234517	SCV001453442	uncertain significance	Alstrom syndrome	2020-01-24	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723822	SCV001955109	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723822	SCV001975614	uncertain significance	not provided		no assertion criteria provided	clinical testing