ClinVar Miner

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

gnomAD frequency: 0.00022  dbSNP: rs372619046
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462849 SCV000541341 uncertain significance Alstrom syndrome 2021-11-06 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 2017-10-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The G1231E variant has not been published as pathogenic or reported as benign to our knowledge. This variant is observed in 10/23918 (0.04%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The G1231E 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 glutamic acid (E) is the wild-type residue at this position in at least two mammalian species. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date are predicted to cause premature protein truncation (Marshall et al., 2012; Stenson et al., 2014).
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.

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