Submissions for variant NM_001378454.1(ALMS1):c.8306C>T (p.Ser2769Phe)

dbSNP: rs1060500037

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463093	SCV000541344	uncertain significance	Alstrom syndrome	2022-06-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2770 of the ALMS1 protein (p.Ser2770Phe). This variant is not present in population databases (gnomAD no frequency). 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: 403937). 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 phenylalanine 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.
GeneDx	RCV000498122	SCV000590285	uncertain significance	not provided	2017-06-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ALMS1 gene. The S2770F variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S2770F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, S2770F is also classified as a variant of uncertain significance in ClinVar by another clinical laboratory (ClinVar SCV000541344.1; Landrum et al., 2016).
Ambry Genetics	RCV002429467	SCV002681951	uncertain significance	Cardiovascular phenotype	2022-01-04	criteria provided, single submitter	clinical testing	The p.S2770F variant (also known as c.8309C>T), located in coding exon 10 of the ALMS1 gene, results from a C to T substitution at nucleotide position 8309. The serine at codon 2770 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000463093	SCV002082902	uncertain significance	Alstrom syndrome	2021-09-30	no assertion criteria provided	clinical testing