Evidence Repository - Clinical Genome Resources

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.1106G>A (p.Arg369Gln)

CA010192

42822 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

Likely Pathogenic

PM6 PM2 PS4 PP1

BP3 BP7 BP5 BP4 PS3 PM4 PM5 PM1 PS1 PS2 PP3 BA1 PVS1 BS3 BS4 BS1

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

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.

PM6

at least 2 de novo occurrences documented;

PM2

Absent from gnomAD

PS4

> 15 probands with DCM

PP1

11 meioses between clinical labs and literature

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

PS3

No functional studies

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.

PS1

No such variant reported in HGMD

PS2

at least 2 de novo, paternity not confirmed occurrences documented

PP3

Revel score score is above threshold but conservation and other tools are discordant

BA1

Absent from gnomad

PVS1

Missense change

BS3

No functional studies

BS4

Variant segregates with disease

BS1

Absent from gnomad

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