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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.5422G>A (p.Gly1808Ser)

CA046762

217468 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6da4c47e-bc70-493e-9b56-bbbf75c63e28
Approved on: 2021-03-22
Published on: 2021-08-25

HGVS expressions

NM_000257.4:c.5422G>A
NM_000257.4(MYH7):c.5422G>A (p.Gly1808Ser)
NC_000014.9:g.23415132C>T
CM000676.2:g.23415132C>T
NC_000014.8:g.23884341C>T
CM000676.1:g.23884341C>T
NC_000014.7:g.22954181C>T
NG_007884.1:g.25530G>A
ENST00000355349.4:c.5422G>A
ENST00000355349.3:c.5422G>A
NM_000257.3:c.5422G>A
More

Uncertain Significance

Not Met criteria codes 15
PS1 PS4 PS3 PP3 PM2 PM5 PM1 PM4 BA1 BS1 BS3 BP4 BP7 BP3 PVS1

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.5422G>A (p.Gly1808Ser) variant in MYH7 has been reported in 3 individuals with HCM (Marsiglia 2013 PMID:24093860; Homburger 2016 PMID:27247418; Invitae pers. comm.), 1 individual with unspecified cardiomyopathy (Invitae pers. comm.) and in 1 individual with sudden cardiac death (Campuzano 2017 PMID:28255936). This variant has also been identified in 0.0045% (FAF 95% CI, 4/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to a lack of sufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): None.
Not Met criteria codes
PS1
No evidence
PS4
Lit - 2 probands (note PM2 not met so did not count): 1 HCM , 1 HCM proband (SHaRe database) Additional lit: 28255936 - 1 SCD (autopsy ruled out HCM) 32 y M, did not count Lab data: Invitae - seen 7 times (5 no info, 1 unspecified cardiomyopathy, 1 HCM)- verified by Kathy Shao, GC at invitae 4/17/20
1 SCD (autopsy ruled out HCM) 32 y M, did not count PubMed:28255936
1 HCM PubMed:27247418
1 hcm PubMed:24093860
PS3
No evidence
PP3
MCAP 0.882 - possible pathogenic REVEL 0.64 7 Damaging, 2 Tolerated, 1 medium
PM2
South Asian: 4/30782 = 0.0001299 = 0.013% FAF = 0.0000443 = 0.00443% ExAC/gnomAD
PM5
No evidence
PM1
does not fall in the head domain (181-937)
PM4
n/a
BA1
South Asian: 4/30782 = 0.0001299 = 0.013% FAF = 0.0000443 = 0.00443% ExAC/gnomAD
BS1
South Asian: 4/30782 = 0.0001299 = 0.013% FAF = 0.0000443 = 0.00443% ExAC/gnomAD
BS3
No evidence
BP4
MCAP 0.882 - possible pathogenic REVEL 0.64 7 Damaging, 2 Tolerated, 1 medium
BP7
n/a
BP3
n/a
PVS1
n/a
Curation History
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