The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.1106G>A (p.Arg369Gln)

CA010192

42822 (ClinVar)

Gene: MYH7
Condition: dilated cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: 64ce5020-8967-4a9e-b432-5a60988016d9
Approved on: 2021-12-22
Published on: 2021-12-22

HGVS expressions

NM_000257.4:c.1106G>A
NM_000257.4(MYH7):c.1106G>A (p.Arg369Gln)
NC_000014.9:g.23429807C>T
CM000676.2:g.23429807C>T
NC_000014.8:g.23899016C>T
CM000676.1:g.23899016C>T
NC_000014.7:g.22968856C>T
NG_007884.1:g.10855G>A
ENST00000355349.4:c.1106G>A
ENST00000355349.3:c.1106G>A
NM_000257.3:c.1106G>A
More

Likely Pathogenic

Met criteria codes 4
PS4 PP1 PM6 PM2
Not Met criteria codes 16
PS1 PS2 PS3 PP3 PVS1 PM4 PM5 PM1 BA1 BS3 BS4 BS1 BP3 BP7 BP5 BP4

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.1106G>A (p.Arg369Gln) variant has been identified in >20 individuals with DCM, including 1 individual who also had LVNC (PS4; Lakdawala 2012 PMID: 22464770; Pugh 2014 PMID:24503780; Klauke 2017 PMID: 29253866; Walsh 2017 PMID: 27532257; Horvat 2019 PMID: 29892087; Quiat 2020 PMID: 32458740; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; Mayo clinic pers. comm.; OMGL pers comm.) and at least 2 individuals with assumed de novo occurrences (PM6; Lakdawala 2012 PMID: 22464770; Quiat 2020 PMID: 32458740; Klauke 2017 PMID: 29253866; LMM pers. comm.). This variant was also identified in >10 individuals with isolated LVNC, including 1 with an assumed de novo occurrence (Dellefave 2009 PMID: 20031619; Hoedemaekers 2010 PMID: 20530761; Tian 2015 PMID: 24691700; Li 2018 PMID: 30371277; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm). This variant segregated with DCM in at least 3 affected individuals from 3 families (PP1; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.), and with LVNC in at least 5 individuals from 4 families (Centenary Institute Sydney pers. comm.; LMM pers. comm.; OMGL pers. comm.) . This variant was absent from large population studies (PM2; http://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 analyses do not provide strong support for or against an impact to the protein. 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, PP1, PM6, PM2.
Met criteria codes
PS4
> 15 probands with DCM
PP1
11 meioses between clinical labs and literature
PM6
at least 2 de novo occurrences documented;
PM2
Absent from gnomAD
Not Met criteria codes
PS1
No such variant reported in HGMD
PS2
at least 2 de novo, paternity not confirmed occurrences documented
PS3
No functional studies
PP3
Revel score score is above threshold but conservation and other tools are discordant
PVS1
Missense change
PM4
Missense change
PM5
No other variants at this residue reported in HGMD
PM1
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 (DCM etc); therefore, PM1 is not applicable.
BA1
Absent from gnomad
BS3
No functional studies
BS4
Variant segregates with disease
BS1
Absent from gnomad
BP3
Missense change
BP7
missense change
BP5
No such case
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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