ClinVar Miner

Submissions for variant NM_031443.4(CCM2):c.665C>T (p.Thr222Met)

gnomAD frequency: 0.00005  dbSNP: rs370245890
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002017274 SCV002295736 uncertain significance Cerebral cavernous malformation 2 2022-09-30 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 CCM2 protein function. ClinVar contains an entry for this variant (Variation ID: 1501181). This variant has not been reported in the literature in individuals affected with CCM2-related conditions. This variant is present in population databases (rs370245890, gnomAD 0.009%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 222 of the CCM2 protein (p.Thr222Met).
Ambry Genetics RCV002642131 SCV003721183 likely benign Inborn genetic diseases 2023-07-20 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV003222377 SCV003918582 uncertain significance not provided 2022-10-13 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

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