Submissions for variant NM_001378454.1(ALMS1):c.7288A>C (p.Ser2430Arg)

gnomAD frequency: 0.00019  dbSNP: rs539112266

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000794034	SCV000933417	uncertain significance	Alstrom syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 2431 of the ALMS1 protein (p.Ser2431Arg). This variant is present in population databases (rs539112266, gnomAD 0.02%). 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: 640904). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195366	SCV001365713	uncertain significance	not specified	2020-03-11	criteria provided, single submitter	clinical testing	The p.Ser2431Arg variant in ALMS1 has not been previously reported in individuals with hearing loss but has been identified in 0.022% (28/128584) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in in ClinVar (Variation ID: 640904). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting.
Baylor Genetics	RCV000794034	SCV001528930	uncertain significance	Alstrom syndrome	2018-07-12	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001849096	SCV002104347	uncertain significance	not provided	2022-03-04	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533, 26582918)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001195366	SCV002571917	uncertain significance	not specified	2022-08-01	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.7285A>C (p.Ser2429Arg), also referred to as c.7291A>C (p.Ser2431Arg) in RefSeq, results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 249412 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.00011 vs 0.0018), allowing no conclusion about variant significance. c.7285A>C has been reported in the literature in at least one heterozygous individual affected with Alstrom Syndrome without strong evidence for causality (e.g. Marshall_2015). This report does not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002386388	SCV002673899	uncertain significance	Cardiovascular phenotype	2023-01-03	criteria provided, single submitter	clinical testing	The p.S2431R variant (also known as c.7291A>C), located in coding exon 8 of the ALMS1 gene, results from an A to C substitution at nucleotide position 7291. The serine at codon 2431 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000794034	SCV002781390	uncertain significance	Alstrom syndrome	2022-03-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000794034	SCV002082863	uncertain significance	Alstrom syndrome	2021-07-27	no assertion criteria provided	clinical testing