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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  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.2649_2651GAA[1] (p.Lys884del)

CA012790

36637 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3cce6484-bb53-4aad-bd72-fd31ad70ba49

HGVS expressions

NM_000257.4:c.2649_2651GAA[1]
NM_000257.4(MYH7):c.2649_2651GAA[1] (p.Lys884del)
ENST00000355349.4:c.2652_2654del
ENST00000355349.3:c.2652_2654del
NM_000257.3:c.2652_2654del
NM_000257.4:c.2652_2654del
NC_000014.9:g.23424798_23424800del
CM000676.2:g.23424798_23424800del
NC_000014.8:g.23894007_23894009del
CM000676.1:g.23894007_23894009del
NC_000014.7:g.22963847_22963849del
NG_007884.1:g.15866_15868del

Uncertain Significance

Met criteria codes 3
PM4_Supporting PS4_Moderate PM2
Not Met criteria codes 12
BS4 BS3 BS1 BP3 BP7 PS3 PS2 PVS1 BA1 PP1 PM6 PM1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.2652_2654delGAA (p.Lys884del) variant in MYH7, also reported as c.2649_2651GAA[1], has been identified in 7 individuals with HCM (PS4_Moderate; Ambry pers comm; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.) and segregated with disease in 1 affected relative with HCM (Invitae pers. comm.). However, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v.2.1.1). This variant is a deletion of 1 amino acid at position 884 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting). In summary, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2; PM4_Supporting.
Met criteria codes
PM4_Supporting
This variant is a deletion of 1 amino acid at position 884 and is not predicted to alter the protein reading-frame. Given that only 1 amino acid has been deleted, the expert panel felt that adjusting to supporting evidence would be more appropriate in this case (PM4_Supporting).
PS4_Moderate
This variant has been identified in 7 individuals with HCM and segregation with HCM in 1 relative (Ambry pers comm, GeneDx pers comm, Invitae pers comm, LMM pers comm). No literature found via Alamut search string in Google Scholar or HGMD Ambry 2 HCM (but only counted 1 since 1 had been tested at another lab) GeneDx 2 HCM Invitae 3 HCM, segregated with HCM in 1 relative from 1 family LMM 1 HCM
PM2
Absent from gnomAD with ~70x coverage on exomes and ~30x coverage on genomes.
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No functional evidence available
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No functional evidence available
PS2
No de novo data
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No literature found via Alamut search string in Google Scholar or HGMD. Invitae observed this variant segregating with HCM in a father and in his affected daughter
PM6
No de novo data
PM1
Rule currently only applicable to missense variants
Approved on: 2021-03-22
Published on: 2021-08-25
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