Variant: NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys)

CA011851

14095 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 7cad6d45-ed00-44b9-a31d-225ff15a0c10

HGVS expressions

NM_000257.3:c.2167C>T
NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys)
NM_000257.4:c.2167C>T
ENST00000355349.3:c.2167C>T
NC_000014.9:g.23425814G>A
CM000676.2:g.23425814G>A
NC_000014.8:g.23895023G>A
CM000676.1:g.23895023G>A
NC_000014.7:g.22964863G>A
NG_007884.1:g.14848C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: PP1_Strong PS4 PP3 PM2 PM5 PM1 PM6 BP2

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.2167C>T (p.Arg723Cys) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:1430197; PMID:27532257; PMID:9829907; PMID:16199542; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). Five of these probands carried additional variants in sarcomere genes (BP2; PMID:20359594; PMID:12707239; Partners LMM ClinVar SCV000059423.5). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:1430197). This variant segregated with disease in 7 affected individuals (PP1_Strong; PMID:9829907; Partners LMM ClinVar SCV000059423.5; AGCMC Sydney ClinVar SCV000212630.1). This variant was identified in 2/66738 European chromosomes (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2167C>G p.Arg723Gly - ClinVar Variation ID 42885). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. The benign evidence code BP2 was not considered to be in conflict with this conclusion given that presence of a second variant can be seen in individuals with cardiomyopathy and may contribute to the severity of disease. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PM6; PP3; BP2

Met criteria codes

• PP1_Strong: 7 segregations including ClinVar SCV000059423.5 and ClinVar SCV000212630.1
• PS4: Variant identified in >20 probands with HCM (including ClinVar SCV000059423.5 and ClinVar SCV000212630.1)
• PP3: Tools suggest damaging
• PM2: 2/66738 European chrs in ExAC
• PM5: c.2167C>G (p.Arg723Gly) - Variation ID 42885 - Pathogenic by Expert Panel
• PM1: Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated
• PM6: 1 de novo occurrence
• BP2: 5 probands with HCM carry additional variants in MYH7 or MYBPC3 (ClinVar SCV000059423.5 and ClinVar SCV000212630.1)

Approved on: 2016-12-15

Published on: 2018-11-16