ClinVar Miner

Submissions for variant NM_000245.4(MET):c.3517A>G (p.Thr1173Ala)

gnomAD frequency: 0.00001  dbSNP: rs779636840
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000811059 SCV000951305 uncertain significance Renal cell carcinoma 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1191 of the MET protein (p.Thr1191Ala). This variant is present in population databases (rs779636840, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 654984). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MET protein function with a negative predictive value of 80%. 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 RCV001020640 SCV001182145 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-22 criteria provided, single submitter clinical testing The p.T1191A variant (also known as c.3571A>G), located in coding exon 16 of the MET gene, results from an A to G substitution at nucleotide position 3571. The threonine at codon 1191 is replaced by alanine, 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.
GeneDx RCV003442100 SCV004170230 uncertain significance not provided 2023-10-13 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in the homozygous state in an individual with autism spectrum disorder (Reale et al., 2021); This variant is associated with the following publications: (PMID: Reale2021[article])
PreventionGenetics, part of Exact Sciences RCV004745605 SCV005347422 uncertain significance MET-related disorder 2024-06-12 no assertion criteria provided clinical testing The MET c.3571A>G variant is predicted to result in the amino acid substitution p.Thr1191Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and, in ClinVar, it is classified as variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/654984). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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