ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1976C>T (p.Thr659Met)

gnomAD frequency: 0.00011  dbSNP: rs199682595
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481060 SCV000572967 uncertain significance not provided 2017-12-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The T660M variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in several other individuals referred for cardiomyopathy genetic testing at GeneDx, although a second variant in the ALMS1 gene was not identified. The T660M variant is also observed in 22/125830 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The T660M 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, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, although 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).
Invitae RCV001070586 SCV001235845 uncertain significance Alstrom syndrome 2022-10-25 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 660 of the ALMS1 protein (p.Thr660Met). This variant is present in population databases (rs199682595, 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: 423290). 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.
Genetic Services Laboratory, University of Chicago RCV001821401 SCV002071389 uncertain significance not specified 2021-03-08 criteria provided, single submitter clinical testing DNA sequence analysis of the ALMS1 gene demonstrated a sequence change, c.1979C>T, in exon 8 that results in an amino acid change, p.Thr660Met. This sequence change has been described in gnomAD with a population frequency of 0.011% (dbSNP rs199682595). The p.Thr660Met change affects a poorly 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.Thr660Met substitution. This sequence change does not appear to have been previously described in patients with ALMS1-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Thr660Met change remains unknown at this time.
Ambry Genetics RCV002420239 SCV002718296 uncertain significance Cardiovascular phenotype 2020-12-08 criteria provided, single submitter clinical testing The p.T660M variant (also known as c.1979C>T), located in coding exon 8 of the ALMS1 gene, results from a C to T substitution at nucleotide position 1979. The threonine at codon 660 is replaced by methionine, 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 RCV001070586 SCV002782716 uncertain significance Alstrom syndrome 2022-04-19 criteria provided, single submitter clinical testing
Natera, Inc. RCV001070586 SCV002080437 uncertain significance Alstrom syndrome 2021-09-28 no assertion criteria provided clinical testing

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