ClinVar Miner

Submissions for variant NM_031443.4(CCM2):c.766G>A (p.Asp256Asn)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003605998 SCV004387419 uncertain significance Cerebral cavernous malformation 2 2023-02-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 256 of the CCM2 protein (p.Asp256Asn). This variant is present in population databases (rs779476016, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CCM2-related conditions. 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. 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.
Clinical Genomics Laboratory, Washington University in St. Louis RCV003605998 SCV005047141 uncertain significance Cerebral cavernous malformation 2 2024-04-01 criteria provided, single submitter clinical testing A CCM2 c.766G>A (p.Asp256Asn) variant was identified at a near heterozygous allelic fraction of 46%, a frequency which may be consistent with germline origin. This variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by one submitter (ClinVar ID: 2790874). It is observed on 11/780,028 alleles in the general population (gnomAD v.4.0.0). Computational predictors suggest that the variant does not impact CCM2 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

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