ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5399C>T (p.Ala1800Val) (rs730880817)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158699 SCV000208634 pathogenic not provided 2015-07-16 criteria provided, single submitter clinical testing This mutation is denoted c.5399 C>T at the cDNA level or p.Ala1800Val (aka A1800V) at the protein level. Ala1800Val in the MYH7 gene has not been reported previously as a disease causing mutation or as a common benign polymorphism to our knowledge. Population studies performed at GeneDx did not detect Ala1800Val in 578 control alleles from individuals of different ethnic backgrounds, suggesting that it is not a common benign variant. Although Ala1800Val represents a conservative amino acid change, the Alanine residue at position 1800 is conserved in this gene throughout evolution. Other pathogenic missense mutations in nearby residues have been reported. Dye et al. (2006) observed a Leu1793Pro mutation in one individual who was diagnosed with myosin storage myopathy. Another nearby missense mutation, Gly1808Ala, was identified in an individual with familial DCM. In patients with Laing distal myopathy, missense mutations have been reported only in exons 32 and 35 of the MYH7 gene and were found to introduce Proline residues that interfere with the coiled-coil formation of the protein. The variant is found in MYH7 panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000214438 SCV000272057 uncertain significance not specified 2015-01-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala1800Va l variant in MYH7 has not been previously reported in individuals with cardiomyo pathy or in large population studies. Alanine (Ala) at position 1800 is highly c onserved in evolution and the change to valine (Val) was predicted to be pathoge nic using a computational tool clinically validated by our laboratory. This tool 's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011 ). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1800Val variant is uncertain.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158699 SCV000280366 likely pathogenic not provided 2012-11-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify it as likely disease causing, and suitable for predictive testing of at-risk family members. This is a novel variant. This is a conservative amino acid change. The Alanine at position 1800 is conserved throughout evolution. Other variants have been reported in association with disease at nearby codons according to HGMD: p.Asp1792Gly (Waldmuller et al 2011; associated with dilated cardiomyopathy), p.Leu1793Pro (Dye et al 2006, Uro-Coste et al 2009; reported in a case of myosin storage myopathy), p.Gln1794Glu (Lakdawala et al 2012; dilated cardiomyopathy); Glu1801Gly (Waldmuller et al. 2011; dilated cardiomyopathy), p.Gly1808Ser (Marsiglia et al 2013; hypertrophic cardiomyopathy), and p.Gly1808Ala (Hershberger et al 2008; dilated cardiomypathy). In silico analysis with PolyPhen2 predicts the variant to be probably damaging. In total this variant has apparently been seen in at least 4 individuals in this family with some sort of cardiomyopathy phenotype including Elijah, his mother (an obligate carrier), his grandfather, and the half-uncle who had a cardiac arrest at the age of seven. Thus we have moderate segregation data in this family. The variant has not been seen in >6700 individuals including GeneDx controls and individuals from population databases. GeneDx did not see this variant in a sample of 289 control individuals of different ethnic backgrounds (unclear how many match the patient’s African American ancestry). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of January, 2014). About 2200 individuals match the patient’s ancestry. The variant is not listed in 1000 Genomes. Based on these data we would consider this variant likely disease causing. The segregation data and absence in >2200 ancestry-matched individuals does support pathogenicity. Further segregation data in the patient's other affected relatives could strengthen confidence in the pathogenicity. The patient’s mother reports that some of her other affected half-sibs have already been tested but we don't have that data.

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