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]
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Variant: NM_000257.4(MYH7):c.5399C>T (p.Ala1800Val)

CA016070

181279 (ClinVar)

Gene: MYH7
Condition: dilated cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2d3bef48-2c10-4eb4-a5bc-72a3180e0eb7

HGVS expressions

NM_000257.4:c.5399C>T
NM_000257.4(MYH7):c.5399C>T (p.Ala1800Val)
NC_000014.9:g.23415155G>A
CM000676.2:g.23415155G>A
NC_000014.8:g.23884364G>A
CM000676.1:g.23884364G>A
NC_000014.7:g.22954204G>A
NG_007884.1:g.25507C>T
ENST00000355349.4:c.5399C>T
ENST00000355349.3:c.5399C>T
NM_000257.3:c.5399C>T

Uncertain Significance

Met criteria codes 3
PP1_Moderate PS4_Supporting PM2
Not Met criteria codes 9
BS3 BP4 PS3 PS1 PS2 PP3 PM1 PM5 PM6

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.5399C>T (p.Ala1800Val) variant has been identified in 2 individuals with DCM (PS4_Supporting; GeneDx pers. comm.; LMM pers. comm.) and segregated with DCM in 6 affected relatives from 1 family (PP1_Moderate; GeneDx pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis did not provide evidence for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy (DCM) in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PP1_Moderate, PM2.
Met criteria codes
PP1_Moderate
Total: 6 segs Lab: 6 segs w/ DCM from 1 family - GeneDx Other: 3 segs (Stanford, same family, cardiomyopathy phenotypes not specified, did not count)
PS4_Supporting
Total: 2 DCM 1 cardiomyopathy-NOS (ClinVar - Stanford submission, didn't count) Lab: 2 (1 DCM-LMM, 1 DCM-GeneDx) No literature in ClinVar No entry in HGMD No hits via Google Scholar
PM2
Absent from ExAC and gnomAD with good coverage
Not Met criteria codes
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Tools are mixed and REVEL is below threshold.
PM1
Variant is outside hotspot domain.
PM5
NM_000257.4(MYH7):c.5398G>C (p.Ala1800Pro) listed in ClinVar as single LP from 2011. Evidence insufficient to warrant full assessment.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-04-27
Published on: 2022-04-27
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