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.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

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

BS3 BS1 PVS1 PS3 PS1 PS4 BP7 BP4 BP3 BA1 PP3 PM1 PM5 PM4 PM2

Evidence Links 3

Expert Panel

Cardiomyopathy VCEP

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.

BS3

No evidence

BS1

South Asian: 4/30782 = 0.0001299 = 0.013% FAF = 0.0000443 = 0.00443% ExAC/gnomAD

PVS1

n/a

PS3

No evidence

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:24093860

1 HCM PubMed:27247418

BP7

n/a

BP4

MCAP 0.882 - possible pathogenic REVEL 0.64 7 Damaging, 2 Tolerated, 1 medium

BP3

n/a

BA1

South Asian: 4/30782 = 0.0001299 = 0.013% FAF = 0.0000443 = 0.00443% ExAC/gnomAD

PP3

MCAP 0.882 - possible pathogenic REVEL 0.64 7 Damaging, 2 Tolerated, 1 medium

PM1

does not fall in the head domain (181-937)

PM5

No evidence

PM4

n/a

PM2

South Asian: 4/30782 = 0.0001299 = 0.013% FAF = 0.0000443 = 0.00443% ExAC/gnomAD

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