Submissions for variant NM_001378454.1(ALMS1):c.2413A>G (p.Thr805Ala)

gnomAD frequency: 0.00001  dbSNP: rs772260271

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665170	SCV000789242	uncertain significance	Alstrom syndrome	2017-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665170	SCV000824918	uncertain significance	Alstrom syndrome	2022-10-05	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 806 of the ALMS1 protein (p.Thr806Ala). This variant is present in population databases (rs772260271, gnomAD 0.06%). 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: 550428). 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	RCV000735886	SCV000864110	uncertain significance	not specified	2017-12-11	criteria provided, single submitter	clinical testing	Variant summary: The ALMS1 c.2410A>G (p.Thr804Ala, alternative name c.2416A>G) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 28/276508 control chromosomes at a frequency of 0.0001013, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALMS1 variant (0.0022361). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).
Ambry Genetics	RCV002442390	SCV002732824	likely benign	Cardiovascular phenotype	2021-04-24	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	RCV000665170	SCV002814081	uncertain significance	Alstrom syndrome	2022-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV003317327	SCV004021385	uncertain significance	not provided	2023-06-27	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