ClinVar Miner

Submissions for variant NM_001318895.3(FHL2):c.678C>A (p.Asn226Lys)

dbSNP: rs137869171
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000156246 SCV000205962 uncertain significance not specified 2013-12-26 criteria provided, single submitter clinical testing The Asn226Lys variant in FHL2 has not been reported in individuals with cardiomy opathy or in large population studies. Asparagine (Asn) at position 226 is not c onserved across evolutionarily distant species and 3 other species (tetradon, pu fferfish and lamprey) have a lysine (Lys, this change) at this position, raising the possibility that change at this position may be tolerated. Computational an alyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, a nd SIFT) suggest that the Asn226Lys variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. Additional i nformation is needed to fully assess the clinical significance of the Asn226Lys variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV001238155 SCV001410954 uncertain significance Primary dilated cardiomyopathy 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 226 of the FHL2 protein (p.Asn226Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FHL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179457). 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 FHL2 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.

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