Submissions for variant NM_001378454.1(ALMS1):c.3290A>G (p.Tyr1097Cys)

gnomAD frequency: 0.00068  dbSNP: rs201816596

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418543	SCV000533094	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560896	SCV000631775	uncertain significance	Alstrom syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1098 of the ALMS1 protein (p.Tyr1098Cys). This variant is present in population databases (rs201816596, 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: 390302). 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.
Genetic Services Laboratory, University of Chicago	RCV001821206	SCV002070952	uncertain significance	not specified	2021-06-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ALMS1 gene demonstrated a sequence change, c.3293A>G, in exon 8 that results in an amino acid change, p.Tyr1098Cys. This sequence change has been described in the gnomAD database with a frequency of 0.19% in the African/African-American subpopulation (dbSNP rs201816596). The p.Tyr1098Cys change affects a moderately conserved amino acid residue located in a domain of the ALMS1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Tyr1098Cys substitution. This sequence change does not appear to have been previously described in patients with ALMS1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Tyr1098Cys change remains unknown at this time.
Ambry Genetics	RCV002323649	SCV002606972	likely benign	Cardiovascular phenotype	2021-07-26	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	RCV000560896	SCV002789646	uncertain significance	Alstrom syndrome	2022-03-04	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000560896	SCV003925067	uncertain significance	Alstrom syndrome	2020-12-09	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000418543	SCV005187747	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000560896	SCV001458920	uncertain significance	Alstrom syndrome	2020-09-16	no assertion criteria provided	clinical testing