Submissions for variant NM_001378454.1(ALMS1):c.3689G>A (p.Gly1230Glu)

gnomAD frequency: 0.00022  dbSNP: rs372619046

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462849	SCV000541341	uncertain significance	Alstrom syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1231 of the ALMS1 protein (p.Gly1231Glu). This variant is present in population databases (rs372619046, gnomAD 0.04%). 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: 403935). 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.
GeneDx	RCV000523577	SCV000618228	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195325	SCV001365669	likely benign	not specified	2019-11-18	criteria provided, single submitter	clinical testing	The p.Gly1231Glu variant in ALMS1 is classified as likely benign due to a lack of conservation across species. Three mammals (rabbit, pika, white rhinoceros) carry a glutamic acid (Glu) at this position. ACMG/AMP Criteria applied: BP4_Strong.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001195325	SCV002041745	likely benign	not specified	2021-11-01	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.3686G>A (p.Gly1229Glu) results in a non-conservative amino acid change located in an Alstrom syndrome repeat (IPR040972) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 149254 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation in the gnomAD database (gnomAD v3.1, genomes dataset). This frequency is somewhat lower than the maximum expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome with Dilated Cardiomyopathy (0.0018), allowing no clear conclusions about variant significance. To our knowledge, no occurrence of c.3686G>A in individuals affected with Alstrom Syndrome with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=2) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001195325	SCV002072008	uncertain significance	not specified	2021-11-29	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ALMS1 gene demonstrated a sequence change, c.3692G>A, in exon 8 that results in an amino acid change, p.Gly1231Glu. This sequence change has been described in the gnomAD database with a frequency of 0.037% in the African/African American subpopulation (dbSNP rs372619046). The p.Gly1231Glu 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.Gly1231Glu substitution. This sequence change does not appear to have been previously described in individuals with ALMS1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly1231Glu change remains unknown at this time.
Ambry Genetics	RCV002348257	SCV002621853	uncertain significance	Cardiovascular phenotype	2023-10-06	criteria provided, single submitter	clinical testing	The p.G1231E variant (also known as c.3692G>A), located in coding exon 8 of the ALMS1 gene, results from a G to A substitution at nucleotide position 3692. The glycine at codon 1231 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is not 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.