Variant: NM_000257.4(MYH7):c.5458C>T (p.Arg1820Trp)

CA016126

181282 (ClinVar)

Gene: MYH7

Condition: MYH7-related late-onset scapuloperoneal muscular dystrophy

UUID: d561f5cc-2dae-449e-b2b5-28ffbaed09b8

Approved on: 2021-06-16

Published on: 2021-06-16

HGVS expressions

NM_000257.4:c.5458C>T
NM_000257.4(MYH7):c.5458C>T (p.Arg1820Trp)
ENST00000355349.4:c.5458C>T
ENST00000355349.3:c.5458C>T
NM_000257.3:c.5458C>T
NC_000014.9:g.23415096G>A
CM000676.2:g.23415096G>A
NC_000014.8:g.23884305G>A
CM000676.1:g.23884305G>A
NC_000014.7:g.22954145G>A
NG_007884.1:g.25566C>T

Uncertain Significance

• Met criteria codes: PP3 PM2

• Not Met criteria codes: BS2 BS4 BS3 BS1 BP7 BP5 BP2 BP4 BP3 BP1 PS2 PS4 PS1 PS3 PP4 PP2 PP1 PM4 PM6 PM5 PM1 PM3 BA1

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.5458C>T (p.Arg1820Trp) variant in MYH7 has been identified in the homozygous state in 2 brothers with myosin storage myopathy exhibiting scapuloperoneal and respiratory weakness as well as dilated cardiomyopathy (Yüceyar 2015 PMID:25666907); however, this data is insufficient to apply the PS4 criterion. This variant was identified in 0.00027% (FAF 95% CI; 2/129152) of Non-Finnish European chromosomes, 0.00142% (FAF 95% CI; 2/24966) of African chromosomes, and 1/19954 of East Asian chromosomes by gnomAD v2.1.1 (PM2; http://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 myosin storage myopathy and cardiomyopathy. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PP3

Met criteria codes

• PP3: Align GVGD = C65, SIFT = Deleterious, Mutation Taster = Disease Causing, PolyPhen 2 = Probably Damaging, REVEL = 0.915
• PM2: Highest filtered allele frequency is 0.00027% in NFE (2/129152 NFE alleles in gnomAD), 0.00142% in African alleles (2/24966 African chromosomes, and 1/19954 East Asian.

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant has been identified as homozygous in 2 brothers with myosin storage myopathy exhibiting scapuloperoneal and respiratory weakness and dilated cardiomyopathy (Yüceyar 2015 PMID:25666907).
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: NM_000257.4(MYH7):c.5458C>G (p.Arg1820Gly) - VUS in ClinVar in 2018 NM_000257.4(MYH7):c.5459G>A (p.Arg1820Gln) - 2* VUS in ClinVar in 2018 Brand et al. Neuromuscul Disord. 2016 Aug;26(8):511-5. PMID: 27282841 Case report of two sisters with MYH7 R1820Q and a TIA1 pathogenic variant. One sister had progressive distal limb weakness but no cardiac involvement. The other sister had mild distal myopathy, supraventricular tachycardia and hypertrophic cardiomyopathy. One sister with only the TIA1 variant had only mild distal myopathy. The more severe phenotype of the sisters with digenic variants was predicted to be caused by the combined impact of both variants. However, pathogenicity of R1820Q is not confirmed by this guideline.
• PM1: (amino acids 181-937) This variant at p.1820 is outside of the PM1 region for MYH7, however Brand et al. PMID: 27282841 suggests that p.R1820Q (different amino acid substitution at same position) may affect the formation of antiparallel myosin molecules in the bare zone, where the complete overlap of the rods is needed, or being the arginine within the titin binding site, a variant at this position could disrupt the binding of myosin to titin.
• PM3: PMID 25666907; detected in the homozygous state in two brothers with myosin storage myopathy (MSM) with scapuloperoneal and respiratory weakness with dilated cardiomyopathy
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline