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

Likely Pathogenic

• Met criteria codes: PM6 PM2 PS4 PP1

• Not Met criteria codes: BA1 PM4 PM5 PM1 BS3 BS4 BS1 BP7 BP5 BP4 BP3 PVS1 PS1 PS2 PS3 PP3

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

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

• 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

Not Met criteria codes

• BA1: Absent from gnomad
• 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.
• BS3: No functional studies
• BS4: Variant segregates with disease
• BS1: Absent from gnomad
• 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
• BP3: Missense change
• PVS1: Missense change
• 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