Variant: NM_000257.4(MYH7):c.343T>C (p.Tyr115His)

CA013702

42960 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 3cd58595-d350-4d2b-ab10-609796d62583

Approved on: 2021-08-25

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.343T>C
NM_000257.4(MYH7):c.343T>C (p.Tyr115His)
NC_000014.9:g.23433086A>G
CM000676.2:g.23433086A>G
NC_000014.8:g.23902295A>G
CM000676.1:g.23902295A>G
NC_000014.7:g.22972135A>G
NG_007884.1:g.7576T>C
ENST00000355349.4:c.343T>C
ENST00000355349.3:c.343T>C
NM_000257.3:c.343T>C

Uncertain Significance

• Met criteria codes: PM2 PS4_Moderate PP3

• Not Met criteria codes: PM6 PM1 PM5 BS4 BS3 BS1 BP2 BP5 BP4 PS2 PS1 PS3 BA1 PP1

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.343T>C (p.Tyr115His) variant in MYH7 has been reported in at least 12 individuals with HCM (PS4_Moderate; Van Driest 2004 PMID:15358028; Homberger 2016 PMID:27247418; Walsh 2017 PMID:27532257; CHEO pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.), 2 of whom also had additional variants in other HCM-associated genes (Invitae pers. comm.; LMM pers. comm.). This variant also segregated with disease in 1 affected relative with HCM (OMGL pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was identified in 0.0009% (1/113572) of European chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2; PP3.

Met criteria codes

• PM2: This variant was identified in 0.0008805% (1/113572) of European (non-Finnish) chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org)
• PS4_Moderate: This variant has been identified in at least 12 individuals with HCM, two of whom had co-occurring variants of uncertain signficance in other genes (personal communication CHEO, Invitae, LMM, and OMGL). This variant has been identified by the Children's Hospital of Eastern Ontario (CHEO) in one individual with HCM, by Invitae in three individuals with HCM (one with a co-occurring VUS), by the Laboratory of Molecular Medicine (LMM) in one individual with HCM (and a co-occurring VUS), and by Oxford Molecular Genetics Laboratory (OMGL) in seven individuals with HCM. Published probands (PMID 27532257, 27247418) not counted due to likely of overlap with LMM and OMGL internal data, and cannot be certain individual from SHaRe database was not included in internal data log. 1 proband counted but not totally considered for PMID 15358028 cohort phenotype is unexplained left ventricular hypertrophy. No proband counted for PMID 30275503, 28606303 primarily modelling paper
• PP3: In silico predicts damaging effect; REVEL concordant

Not Met criteria codes

• PM6: no evidence
• PM1: Located outside designated PM1 region (codons 181-937)
• PM5: no variants in same codon
• BS4: n/a
• BS3: no functional studies
• BS1: This variant was identified in 0.0008805% (1/113572) of European (non-Finnish) chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org)
• BP2: n/a
• BP5: not applicable
• BP4: In silico predicts damaging effect; REVEL concordant
• PS2: no evidence
• PS1: no variants in same codon
• PS3: no functional studies
• BA1: This variant was identified in 0.0008805% (1/113572) of European (non-Finnish) chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org)
• PP1: This variant has been identified by the Oxford Molecular Genetics Laboratory in 7 individuals with HCM and segregated with disease in one affected family member.