ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1208G>T (p.Arg403Leu) (rs121913624)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158679 SCV000208614 pathogenic not provided 2017-03-24 criteria provided, single submitter clinical testing p.Arg403Leu (R403L) CGG>CTG: c.1208 G>T in exon 13 of the MYH7 gene (NM_000257.2). The Arg403Leu mutation has been reported in several studies in association with HCM. Richard et al. (2003) found that this mutation, which affects a highly conserved residue, co-segregated with HCM in affected members of a family, and was not present in 200 chromosomes of control individuals.3 In addition, two other missense mutations affecting the same Arginine 403 codon, Arg403Trp (R403W) and Arg403Gln (R403Q) , have been reported previously in association with HCM, further supporting the functional importance of this region of the protein. The variant is found in MYH7 panel(s).
OMIM RCV000015157 SCV000035414 pathogenic Familial hypertrophic cardiomyopathy 1 1993-12-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158679 SCV000280296 likely pathogenic not provided 2015-06-16 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. p.Arg403Leu (c.1208G>T) in MYH7 Based on the data reviewed below we consider this variant likely disease-associated. The variant has been seen in at least 3 unrelated cases of HCM with strong segregation data. The variant was first reported by Dausse et al (1993) in a large kindred in which linkage studies including 11 affected relatives pointed towards MYH7. Sequencing of MYH7 identified p.Arg403Leu and its presence was confirmed in 6 affected individuals. A subsequent publication that included some of the same authors reported an additional family that appears to be distinct from the initial report (Al-Mahdawi et al 1994). Three affected individuals and one obligate carrier carried p.Arg403Leu. Richard et al (2003) reported the variant in one individual with HCM. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 403 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg403Gln and p.Arg403Trp, both very likely disease cuausing) and nearby codons (p.Arg404Leu, p.Arg404Met, p.Arg406Met, p.Arg407Val). Moolman et al (1993) noted that there is a CpG doublet at codon 403 which may likely makes it susceptible to mutation. In total the variant has not been seen in 5150 published controls and publicly available population datsets. There is no variation at codon 403 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in 1000 genomes (as of 1/14/2012). p.Arg403Gln is not listed in dbSNP (as of 1/14/2012). The variant was not observed in the following published control samples: 50 (Al-Mahdawi et al 1994), 100 (Richard et al 2003).

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