ClinVar Miner

Submissions for variant NM_000245.4(MET):c.199A>G (p.Thr67Ala)

gnomAD frequency: 0.00001  dbSNP: rs202047059
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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 RCV001052646 SCV001216867 uncertain significance Renal cell carcinoma 2023-08-30 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 41621). This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is present in population databases (rs202047059, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 67 of the MET protein (p.Thr67Ala).
Ambry Genetics RCV002415458 SCV002721782 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-09 criteria provided, single submitter clinical testing The p.T67A variant (also known as c.199A>G), located in coding exon 1 of the MET gene, results from an A to G substitution at nucleotide position 199. The threonine at codon 67 is replaced by alanine, an amino acid with similar properties. This variant was detected as a secondary finding in 1 out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108). This amino acid position is poorly 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 RCV000034526 SCV005419436 uncertain significance not provided 2024-05-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with atherosclerosis (PMID: 22703879); This variant is associated with the following publications: (PMID: 22703879)
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000034526 SCV000043292 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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