Variant: NM_000257.4(MYH7):c.323G>A (p.Arg108His)

CA013482

181299 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: e158be0b-78ae-458c-8a17-923e322eecc3

Approved on: 2021-11-19

Published on: 2021-12-09

HGVS expressions

NM_000257.4:c.323G>A
NM_000257.4(MYH7):c.323G>A (p.Arg108His)
NC_000014.9:g.23433106C>T
CM000676.2:g.23433106C>T
NC_000014.8:g.23902315C>T
CM000676.1:g.23902315C>T
NC_000014.7:g.22972155C>T
NG_007884.1:g.7556G>A
ENST00000355349.4:c.323G>A
ENST00000355349.3:c.323G>A
NM_000257.3:c.323G>A

Uncertain Significance

• Met criteria codes: PP3 PM2

• Not Met criteria codes: BS4 BS3 BS1 BP5 BP2 BP4 PS3 BA1 PS2 PS4 PS1 PP1 PM6 PM1 PM5

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.323G>A (p.Arg108His) variant has been identified in 2 individuals with DCM, including 1 that also had LVNC and another that had a truncating variant in TTN (GeneDx pers. comm.; OMGL pers. comm.), as well as in 1 individual with LVNC (Ambry pers. comm.). However, collectively this data is insufficient to apply PS4. Additionally, this variant segregated with disease in 1 affected individual with DCM and LVNC from 1 families (OMGL pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, 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 dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3

Met criteria codes

• PP3: PROVEAN, Alamut and SIFT all predict a damaging effect. REVEL score is 0.844, predicting a damaging effect. Polyphen predicted benign below, but Sarcomere Polyphen is PATH (Jordan D. M., Kiezun, A., Baxter, S. M., Agarwala, V., Green, R. C., Murray, M. F., Pugh, T., Lebo, M. S., Rehm, H. L., Funke, B. H., Sunyaev, S. R. Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. Am. J. Hum. Genet. 88, 183-92 (2011)).
• PM2: Variant absent in GnomAD, in a region with good coverage (more than 251000 alleles) (assessed 3/10/2021)

Not Met criteria codes

• 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
• BP5: One patient reported with DCM and a TTNtv in the A-band
• 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
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: 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: Variant seen in 2 individuals with DCM, including 1 that also had LVNC and another with a second variant sufficient to explain disease (OMGL & GeneDx); Variant also seen in an individual with LVNC only. No literature in ClinVar, Google, or via other searches.
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: One segregation reported in a pair of affected proband and father (DCM & LVNC phenotype)
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Variant NOT located in the head domain (codons 181-937; Walsh et al. PMID: 27532257)
• PM5: R108C reported in ClinVar does not reach the pathogenic classification (it is a variant of uncertain significance)