Variant: NM_000257.4(MYH7):c.5134C>T (p.Arg1712Trp)

CA015719

14118 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 0fba9f4e-9716-4bd7-ab0b-8985781f4575

HGVS expressions

NM_000257.4:c.5134C>T
NM_000257.4(MYH7):c.5134C>T (p.Arg1712Trp)
NC_000014.9:g.23415652G>A
CM000676.2:g.23415652G>A
NC_000014.8:g.23884861G>A
CM000676.1:g.23884861G>A
NC_000014.7:g.22954701G>A
NG_007884.1:g.25010C>T
ENST00000355349.4:c.5134C>T
ENST00000355349.3:c.5134C>T
NM_000257.3:c.5134C>T
NR_126491.1:n.84G>A

Likely Pathogenic

• Met criteria codes: PM2 PS4_Moderate PP3 PP1_Moderate

• Not Met criteria codes: PM5 PM6 PM1 PM4 BA1 BS4 BS3 BS1 BP5 BP2 BP7 BP4 PS1 PS2 PS3 PP4

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.5134C>T (p.Arg1712Trp) variant in MYH7 has been reported in the heterozygous state in at least 13 individuals with HCM, 2 of whom also had additional variants in other HCM-associated genes (PS4_Moderate; Hougs 2005 PMID:15483641; Gruner 2011 PMID:21511876; Jensen 2013 PMID:23197161; Hagen 2013 PMID:24498601; Mu 2019 https://www.actamedicamediterranea.com/archive/2019/medica-5/pathogenic-mutation-detection-and-correlation-analysis-between-genotype-and-phenotype-of-familial-hypertrophic-cardiomyopathy-in-chinese-han-nationality/pdf; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with HCM in at least 6 affected relatives from 4 families (PP1_Moderate; Hougs 2005 PMID:15483641; Mu 2019; Ambry pers comm.; Centenary Institute Sydney pers comm.). This variant has also been identified in the homozygous state in 2 siblings from a consanguineous family with myopathy and normal cardiac function (Beecroft 2019 PMID:31130376). Data from the gnomAD population database (v2.1.1) is insufficient to assess the frequency of this variant; however, this variant is absent from the ExAC database (PM2; http://gnomad.broadinstitute.org; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate; PP1_Moderate; PM2; PP3.

Met criteria codes

• PM2: Absent from gnomAD. 250,888 alleles with coverage at this position. (Filter applies to denote no confidence in genotype calls, but variant is absent from exac -HZ)
• PS4_Moderate: 13 probands with HCM: 4 probands in the literature + 9 probands reported in internal data from VCC labs (1 Ambry, 1 CHEO, 1 GeneDx, 2 Invitae, 2 LMM, 1 OMGL, 1 Sydney)
• PP3: Highly conserved. SIFT, PolyPhen2 , and REVEL predict deleterious.
• PP1_Moderate: 3 affected segregations reported by VCC labs (Ambry: 2 affected family member with variant, 3 first degree relatives without variant and reportedly healthy; Sydney: 1 from Sydney). The family reported in Hougs 2005 may contain up to 6 affected segregations - see below for caveat. Family from MU 4 segregations. Due to uncertainty of these individuals being affected, I kept the evidence strength as Moderate

Not Met criteria codes

• PM5: Note that NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln) is classified as likely pathogenic by the expert panel in ClinVar. Evidence not applied because classification is likely path vs path.
• PM6: Never been reported as de novo
• PM1: Not in the myosin head domain
• PM4: missense variant
• BA1: Absent from gnomAD. 250,888 alleles with coverage at this position. (Filter applies to denote no confidence in genotype calls, but variant is absent from exac -HZ)
• BS4: No obviously affected individuals without this variant in reported pedigrees.
• BS3: Relevant functional studies not reported
• BS1: Absent from gnomAD. 250,888 alleles with coverage at this position. (Filter applies to denote no confidence in genotype calls, but variant is absent from exac -HZ)
• BP5: Not found in a case with alternate molecular basis for disease
• BP2: Not seen in combination with a pathogenic variant.
• BP7: N/A
• BP4: Highly conserved. SIFT, PolyPhen2 , and REVEL predict deleterious.
• PS1: Same amino acid change from a different nucleotide change has not been reported at this position.
• PS2: Never been reported as de novo
• PS3: Relevant functional studies not reported
• PP4: N/A

Approved on: 2021-06-16

Published on: 2021-06-16