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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  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.2711G>A (p.Arg904His)

CA012913

42926 (ClinVar)

Gene: MYH7
Condition: dilated cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 87568204-0e45-42e8-b9e9-3488c811c4d5

HGVS expressions

NM_000257.4:c.2711G>A
NM_000257.4(MYH7):c.2711G>A (p.Arg904His)
ENST00000355349.4:c.2711G>A
ENST00000355349.3:c.2711G>A
NM_000257.3:c.2711G>A
NC_000014.9:g.23424118C>T
CM000676.2:g.23424118C>T
NC_000014.8:g.23893327C>T
CM000676.1:g.23893327C>T
NC_000014.7:g.22963167C>T
NG_007884.1:g.16544G>A

Pathogenic

Met criteria codes 5
PS4 PM6_Strong PP1_Strong PP3 PM2
Not Met criteria codes 10
BS3 BS4 BP4 BP1 PS1 PS2 PS3 PP2 PM1 PM5

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.2711G>A (p.Arg904His) variant has been identified in at least 14 individuals with DCM in the literature (PS4; Waldmüller 2011 PMID:21750094; Lakdawala 2012 PMID:22464770; Pugh 2014 PMID:24503780; Chami 2014 PMID:25448463; Walsh 2017 PMID:27532257; Gigli 2019 PMID:31514951; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.). In 3 of theses cases, the variant was identified as an unconfirmed de novo occurrence (PM6_Strong; Lakdawala 2012 PMID:22464770; GeneDx pers. comm.; OMGL pers. comm.). This variant also segregated with disease in 7 affected individuals with DCM across 4 families (PP1_Strong; Chami 2014 PMID:25448463; GeneDx pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). While this variant lies in the head region of the protein (aa 181-937), where missense variants 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. Finally, 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 pathogenic for dilated cardiomyopathy (DCM) in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PM6_Strong, PP1_Strong, PM2, PP3.
Met criteria codes
PS4
At least 14 individuals with DCM in the literature (Waldmüller 2011 PMID:21750094; Lakdawala 2012 PMID:22464770; Pugh 2014 PMID:24503780; Chami 2014 PMID:25448463; Walsh 2017 PMID:27532257; Gigli 2019 PMID:31514951; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.). Verified with Kate Thomson that OMGL is proband with DCM and variant was found in all 3 affected children with DCM. Invitae: Only counting 2 (1 with nonischemic CM and 1 with DCM) 1 with Nonischemic cardiomyopathy 1 with LVNC plus a VUS in MYH6 and a VUS in DSP 1 with sudden cardiac death and suspected DCM, also has a Pathogenic exons 8-9 deletion in SGCD (only a suggested association with DCM) 1 with DCM, also has a VUS in RYR2 (not associated with DCM) Ambry: Single proband with LVNC and DCM. GeneDx: 5 cases with DCM (2 de novo w/o parental identity confirmed; 3 segregations with DCM in 2 families) 4 internal probands referred for cardiomyopathy panels - Infant Cauc female dx with DCM at 3 weeks of age, de novo without confirmed maternity and paternity in this patient - Infant male dx with DCM and cardiogenic shock at birth, de novo without confirmed maternity and paternity in this patient - Infant male dx with DCM as newborn- segregation in mother dx with DCM and sibling dx with DCM - Male dx with severe DCM and apical LVNC at 19mo, multiple other variants identified and no segregation studies We have also seen this variant in an exome case of a female with DCM, inherited from a mother with DCM All literature entries from Neel Gadhoke should be ignored for the sake of this assessment.
PM6_Strong
De novo in 2 GeneDx cases with DCM Assumed de novo variant in DCM patient (Lakdawala 2012 PMID:22464770 - an LMM patient)
PP1_Strong
Variant segregated with DCM in 7 affected relative from 4 families (Chami 2014 PMID:25448463; GeneDx pers. comm.; OMGL pers. comm.) Variant was also absent from 2 unaffected relatives.
PP3
All tools, including REVEL, support an impact and variant is conserved.
PM2
Absent from gnomAD with ~30x genome and ~90x exam coverage
Not Met criteria codes
BS3
No evidence
BS4
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
BP1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No evidence
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Hotspot/est. functional domain (amino acids 181-937) without benign variation; But variant is predominantly DCM, so cannot use
PM5
p.Arg904Pro - 1* VUS in ClinVar; Not in HGMD (not evaluated) p.Arg904Cys - 2* VUS in ClinVar; VCC assessment in VCI is LP for DCM QUESTION: Can PM5 be used for other diseases?
Approved on: 2021-09-27
Published on: 2021-10-01
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