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.611G>A (p.Arg204His)

CA016546

43095 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 958803e7-017c-44a6-ba70-55cbb312a9e7
Approved on: 2022-04-27
Published on: 2022-04-27

HGVS expressions

NM_000257.4:c.611G>A
NM_000257.4(MYH7):c.611G>A (p.Arg204His)
NC_000014.9:g.23431789C>T
CM000676.2:g.23431789C>T
NC_000014.8:g.23900998C>T
CM000676.1:g.23900998C>T
NC_000014.7:g.22970838C>T
NG_007884.1:g.8873G>A
ENST00000355349.4:c.611G>A
ENST00000355349.3:c.611G>A
NM_000257.3:c.611G>A

Likely Pathogenic

Met criteria codes 4
PS4 PP1 PM1 PM2
Not Met criteria codes 16
BS4 BS3 BS1 BP5 BP2 BP7 BP4 PS3 PS2 PS1 PP3 PVS1 PM6 PM4 PM5 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The NM_000257.4(MYH7):c.611G>A (p.Arg204His) variant has been identified in at least >45 individuals with HCM, at least 7 of whom had disease-causing variants in other cardiomyopathy associated genes (PS4; Richard 2003 PMID:12707239; Funada 2010 PMID:20975235; Berge 2014 PMID:24111713; Homburger 2016 PMID: 27247418; Ntusi 2016 PMID:27841901; Walsh 2017 PMID: 27532257; Burns 2017 PMID:28790153; Mattivi 2020 PMID:32894683; 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 4 affected relatives from 4 families (PP1; GeneDx pers. comm.; OMGL pers. comm.). This variant was identified in 0.0006% (FAF 95% CI; 3/129190) of European 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 missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis did not provide evidence for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PP1, PM2, PM1.
Met criteria codes
PS4
Variant identified in at least >45 individuals with hypertrophic cardiomyopathy (HCM), at least 7 of which had disease-causing variants in other genes (PS4; Richard 2003 PMID:12707239; Funada 2010 PMID:20975235; Berge 2014 PMID:24111713; Homburger 2016 PMID: 27247418; Ntusi 2016 PMID:27841901; Walsh 2017 PMID: 27532257; Burns 2017 PMID:28790153; Mattivi 2020 PMID:32894683; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). Invitae data: 8 HCM with the following additional details 1 HCM proband also has hypertension 1 proband also has ABCG8 p.Asp19His increased risk allele 1 HCM proband also has CANA1C p.Arg518His (Pathogenic) & FLNC p.Ile2078Thr 1 proband also has DMD deletion of exons 49-51 (Pathogenic); 1 HCM proband has 2 FLNC variants (p.Glu1128Lys and p.Ala1588Gly) and 1 TNNI3 p.Arg69Alafs*8 variant LMM data: 5 HCM with the following additional details 1 HCM proband with Afib had a LP path variant in MYH7 (p.Arg1045Leu) 1 HCM proband also has fs variant in MYBPC3 (p.Ala181CysfsX53) The LVH proband (not included in the HCM total) had a LOF splice variant in PKP2 (2146_1G>C) adn a VUS in DSP Literature search complete for ClinVar, HGMD, and Google Scholar.
PP1
4 segregations with HCM from 4 families (GeneDx pers. comm.; OMGL pers. comm.)
PM1
Within myosin head domain
PM2
gnomAD 5 alleles; 0 homozygotes; 0.00002% 3/129,190 Europeans FAF 6.3e-06 5/282,888 Overall FAF 6.9e-06 FAF for Euro Exomes 0.000002920 (4/251488)
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
A number of reported cases have other variants of potential significance to their phenotype
BP2
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
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No instances of different nucleotide changes resulting in the same AA change identified.
PP3
Computational tools are mixed and REVEL is below the threshold.
PVS1
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
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
NM_000257.4(MYH7):c.611G>T (p.Arg204Leu) - Multiple conflicting entries NM_000257.4(MYH7):c.610C>T (p.Arg204Cys) - 2* VUS NM_000257.4(MYH7):c.610C>A (p.Arg204Ser) - 1* VUS Not additional evaluation needed.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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