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.3883G>A (p.Glu1295Lys)

CA014200

181236 (ClinVar)

Gene: MYH7
Condition: cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 01cf27a5-33c1-4319-9c90-5f064232265b
Approved on: 2021-11-19
Published on: 2021-12-09

HGVS expressions

NM_000257.4:c.3883G>A
NM_000257.4(MYH7):c.3883G>A (p.Glu1295Lys)
NC_000014.9:g.23419266C>T
CM000676.2:g.23419266C>T
NC_000014.8:g.23888475C>T
CM000676.1:g.23888475C>T
NC_000014.7:g.22958315C>T
NG_007884.1:g.21396G>A
ENST00000355349.4:c.3883G>A
ENST00000355349.3:c.3883G>A
NM_000257.3:c.3883G>A

Uncertain Significance

Met criteria codes 2
PP3 PM2
Not Met criteria codes 19
PS3 PS2 PS4 PS1 PP1 PM6 PM1 PM4 PM5 BA1 PVS1 BS4 BS3 BS1 BP3 BP5 BP2 BP7 BP4

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.3883G>A (p.Glu1295Lys) variant has been identified in 1 individual with LVNC, in 1 individual with congestive heart failure and 1 individual with sudden cardiac arrest (GeneDx pers. comm., Invitae pers. comm.); however, due to the nature of the associated phenotypes, this data is insufficient to apply the PS4 criterion. This variant was identified in 0.002% (FAF 95% CI; 3/34592) of Latino/Admixed American chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3.
Met criteria codes
PP3
REVEL = 0.822, greater than internal threshold of 0.7
PM2
gnomAD FAF 0.002298%
Not Met criteria codes
PS3
no functional studies reported
PS2
No de novo occurrences reported
PS4
No probands reported with HCM or DCM
PS1
no other variants at this position reported in HGMD or ClinVar
PP1
No segregations reported
PM6
No de novo occurrences reported
PM1
Not in myosin head domain
PM4
Protein length does not change
PM5
no other variants at this position reported in HGMD or ClinVar
BA1
gnomAD FAF 0.002298%
PVS1
Not a null variant
BS4
No segregations reported
BS3
no functional studies reported
BS1
gnomAD FAF 0.002298%
BP3
N/A for MYH7
BP5
Not found in a case with a pathogenic variant in a different gene.
BP2
Not reported in case with other pathogenic variant
BP7
Not a silent or intronic variant
BP4
REVEL = 0.822, greater than internal threshold of 0.7
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