ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.842G>C (p.Arg281Thr) (rs730880856)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158768 SCV000208703 likely pathogenic not provided 2017-05-23 criteria provided, single submitter clinical testing The Arg281Thr variant in the MYH7 gene has been reported in a large family with noncompaction of the ventricular myocardium (NVM). Budde B et al. (2007) reported that the Arg281Thr variant co-segregated with a noncompaction phenotype in the family with high clinical variability. Arg281Thr occurs in a conserved region of the protein, and in silico programs predict the variant destabilizes the myosin head. In many individuals in the family, other heart defects were seen along with noncompaction, including Ebstein's anomaly. Furthermore, the NHLBI ESP Exome Variant Server reports Arg281Thr was not observed in approximately 6,500 samples from individuals of European and African America backgrounds, indicating it is not a common benign variant in these populations. Based on currently available evidence, R281T is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000219555 SCV000271413 pathogenic Left ventricular noncompaction 2015-02-03 criteria provided, single submitter clinical testing The p.Arg281Thr variant in MYH7 has been reported in 1 German individual with LV NC, Ebstein's anomaly and ASD, and segregated with disease in 10 affected relati ves (Budde 2007). This variant has also been identified in 1 individual with HCM (Waldmuller 2008), and was absent from large population studies. Arginine (Arg) at position 281 is highly conserved in evolution, and the change to threonine ( Thr) was predicted to be pathogenic using a computational tool clinically valida ted by our laboratory. This tool's pathogenic prediction is estimated to be corr ect 94% of the time (Jordan 2011). In summary, this variant meets our criteria t o be classified as pathogenic (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies and absence from controls.

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