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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.457del (p.His153fs)

CA015125

43028 (ClinVar)

Gene: MYH7
Condition: cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c037248d-f169-4be4-a662-bbff61536797
Approved on: 2021-08-25
Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.457del
NM_000257.4(MYH7):c.457del (p.His153fs)
ENST00000355349.4:c.457del
ENST00000355349.3:c.457del
NM_000257.3:c.457del
NC_000014.9:g.23432687del
CM000676.2:g.23432687del
NC_000014.8:g.23901896del
CM000676.1:g.23901896del
NC_000014.7:g.22971736del
NG_007884.1:g.7978del
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Uncertain Significance

Met criteria codes 1
PM2
Not Met criteria codes 11
BA1 PS3 PS2 PS4 PP1 PVS1 PM6 BS4 BS3 BS1 BP5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.457del (p.His153Thrfs*14) variant in MYH7 has been identified in a 6 month old with DCM that also had a second variant in MYH7 (LMM pers comm) as well as 2 cases in the literature without clinical information (Ceyhan-Birsoy 2019 PMID: 30609409; Zimmerman 2010 PMID: 20474083), which is insufficient to apply PS4_Supporting. This variant has been identified in 0.000879% (1/113760) of European (Non-Finnish) chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift leading to a truncated or absent protein and the contribution of LOF variants in MYH7 to autosomal dominant inherited cardiomyopathy is incompletely understood. In summary, due to a lack of 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.
Met criteria codes
PM2
Variant identified in 0.000879% (1/113760) of European (Non-Finnish) chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org)
Not Met criteria codes
BA1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant has been reported in 2 cases in the literature: Ceyhan-Birsoy O. 2019 PMID: 30609409 - Variant found in 1 NICU case as part of BabySeq study, but no clinical information provided Zimmerman R.S. 2010 PMID: 20474083 - Variant found in cohort of DCM cases, but no specifics of case provided (included LMM data). LMM internal data - 6 month old with DCM that carries a VUS-Favor Benign in MYH7 as well. May be same case as published it literature (LMM contribution on publication).
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
Currently assessing for autosomal dominant disease. However, heterozygous loss-of-function (LOF) variants in MYH7, such as this variant, are not believed to be pathogenic for the dominant condition more classically associated to MYH7, when a LOF variant is found in trans with another variant affecting function, a more severe and early-onset cardiomyopathy presentation can occur (LMM unpublished data).
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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