Submissions for variant NM_001378454.1(ALMS1):c.7288A>G (p.Ser2430Gly)

dbSNP: rs539112266

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000430965	SCV000532989	uncertain significance	not provided	2016-10-24	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ALMS1 gene. The S2431G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S2431G variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S2431G 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. Subsequently, although this substitution occurs at a position where amino acids with similar properties to serine are tolerated across species, G2431 is not tolerated. Splicing algorithims predict that this change may create a cryptic splice donor site that is upstream of the natural donor site, however, functional studies are necessary to determine the consequences of this change. Lastly, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date introduce a premature termination codon (Marshall et al., 2012; Stenson et al., 2014).
Invitae	RCV001272961	SCV001507076	uncertain significance	Alstrom syndrome	2022-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2431 of the ALMS1 protein (p.Ser2431Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 390212). 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.
Ambry Genetics	RCV002379369	SCV002671552	uncertain significance	Cardiovascular phenotype	2022-04-19	criteria provided, single submitter	clinical testing	The p.S2431G variant (also known as c.7291A>G), located in coding exon 8 of the ALMS1 gene, results from an A to G substitution at nucleotide position 7291. The serine at codon 2431 is replaced by glycine, an amino acid with similar 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.
Fulgent Genetics, Fulgent Genetics	RCV001272961	SCV002814010	uncertain significance	Alstrom syndrome	2022-04-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001272961	SCV001455468	uncertain significance	Alstrom syndrome	2020-03-11	no assertion criteria provided	clinical testing