Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000257.4(MYH7):c.709C>T (p.Arg237Trp)

CA016662

43098 (ClinVar)

Gene: MYH7
Condition: dilated cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3d1f89e6-db54-4239-a326-7ac5ba99f734

HGVS expressions

NM_000257.4:c.709C>T
NM_000257.4(MYH7):c.709C>T (p.Arg237Trp)
NC_000014.9:g.23431608G>A
CM000676.2:g.23431608G>A
NC_000014.8:g.23900817G>A
CM000676.1:g.23900817G>A
NC_000014.7:g.22970657G>A
NG_007884.1:g.9054C>T
ENST00000355349.4:c.709C>T
ENST00000355349.3:c.709C>T
NM_000257.3:c.709C>T

Likely Pathogenic

Met criteria codes 5
PM6_Supporting PS4_Moderate PP1 PP3 PM2
Not Met criteria codes 12
PS2 PS1 PS3 BA1 BS2 PM1 PM5 BS4 BS3 BS1 BP5 BP2

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The NM_000257.4(MYH7):c.709C>T (p.Arg237Trp) variant has been identified in at least 10 individuals with DCM, 3 of whom also carried other disease-causing variants (PS4_Moderate; Hershberger 2008 PMID:19412328; Pugh 2014 PMID:24503780; Walsh 2017 PMID:27532257; Franaszczyk 2017 PMID:28045975; Dal Ferro 2017 PMID:28416588; Gigli 2019 PMID:31514951; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant has also been identified in 2 individuals with unspecified cardiomyopathy, 1 individual with LVNC, and 1 with ventricular tachycardia (GeneDx pers. comm.; Invitae pers. comm.). This variant has been reported as de novo in 1 individual with sudden death and suspected HCM based on autopsy (PM6_supporting; Ambry pers. comm.); however, because the reported phenotype is not specific enough, the PM6 criterion was downgraded to PM6_supporting. This variant segregated with disease in 3 affected individuals with DCM in 1 family (LMM pers. comm.). In vitro functional studies provide some evidence that this variant impacts protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Ujfalusi 2018 PMID:29666183; Liu 2018 PMID:29867217). This variant was identified in 0.0023% (FAF 95% CI; 3/34592) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. 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 dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM6_Supporting, PM2, PP3.
Met criteria codes
PM6_Supporting
Ambry reports one de novo occurrence, however they indicate that the case is a proband with SD during sleep and HCM suspected on autopsy. Cannot apply PM6 without clear phenotype?
PS4_Moderate
Identified in 11 probands with dilated cardiomyopathy - 1 proband also had a TTN truncating variant c.78439C>T (not in ClinVar, A-band) - 2 probands had LP/P variants in MYBPC3 and MT-ND1 (no details provided) Also seen in - 2 proband (not counted towards the total) with suspected DCM from GeneDx - 1 proband with LVNC - 1 proband with VT - Ambry reports one de novo occurrence, however they indicate that the case is a proband with SD during sleep and HCM suspected on autopsy. Hershberger 2008 PMID:19412328; Pugh 2014 PMID:24503780; Walsh 2017 PMID:27532257; Franaszczyk 2017 PMID:28045975; Dal Ferro 2017 PMID:28416588; Gigli 2019 PMID:31514951; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.
PP1
Segregated with disease in 3 relatives with DCM from 1 family (LMM pers. comm.)
PP3
SIFT, PolyPhen, MutationTaster, and Provean, all predict a damaging effect. This is consistent with the results from REVEL.
PM2
This variant was identified in 0.0023% (FAF 95% CI; 3/34592) of Latino/Admixed American chromosomes in gnomAD. Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting.
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
Please review both papers below to determine if studies are eligible for consideration towards this rule. PMID: 29666183 and PMID: 29867217 - I do not understand the implications of the results In vitro and in silico functional studies provide some evidence that this variant impacts protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Ujfalusi 2018 PMID:29666183; Liu 2018 PMID:29867217).
Measure the detachment rate of single molecules of human β-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds. PubMed:29867217
Detailed biochemical characterization and mechanochemical cycle modeling of recombinant human β-cardiac myosin motor domains carrying five DCM mutations, including R237W. PubMed:29666183
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Missense variant located in the head domain (codons 181-937; Walsh et al. PMID: 27532257), but only applicable for HCM and this is predominantly a DCM variant.
PM5
Arg237Gln present in HGMD, however it is DM? and the classification does not reach PATH. It is consistently reported as VUS in ClinVar (2* VUS).
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
Measure the detachment rate of single molecules of human β-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds. PubMed:29867217
Detailed biochemical characterization and mechanochemical cycle modeling of recombinant human β-cardiac myosin motor domains carrying five DCM mutations, including R237W. PubMed:29666183
BS1
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
Approved on: 2022-07-30
Published on: 2022-07-30
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