NM_000257.4(MYH7):c.745C>T (p.Arg249Ter) AND Cardiomyopathy

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Sep 9, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003532128.6

Allele description [Variation Report for NM_000257.4(MYH7):c.745C>T (p.Arg249Ter)]

NM_000257.4(MYH7):c.745C>T (p.Arg249Ter)

Gene:

MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.745C>T (p.Arg249Ter)

HGVS:

NC_000014.9:g.23431469G>A
NG_007884.1:g.9193C>T
NM_000257.4:c.745C>TMANE SELECT
NP_000248.2:p.Arg249Ter
LRG_384:g.9193C>T
NC_000014.8:g.23900678G>A
NM_000257.3:c.745C>T

Protein change:

R249*

Links:

dbSNP: rs730880852

NCBI 1000 Genomes Browser:

rs730880852

Molecular consequence:

NM_000257.4:c.745C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004356969	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 9, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28798025, 25741868
SCV004822528	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 9, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28798025, 25741868
SCV004848035	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 8, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28798025, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004356969

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 9, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004822528

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 9, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004848035

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Feb 8, 2019)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	143475	not provided	clinical testing

Citations

PubMed

Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.

Miszalski-Jamka K, Jefferies JL, Mazur W, Głowacki J, Hu J, Lazar M, Gibbs RA, Liczko J, Kłyś J, Venner E, Muzny DM, Rycaj J, Białkowski J, Kluczewska E, Kalarus Z, Jhangiani S, Al-Khalidi H, Kukulski T, Lupski JR, Craigen WJ, Bainbridge MN.

Circ Cardiovasc Genet. 2017 Aug;10(4). doi: 10.1161/CIRCGENETICS.117.001763.

PubMed [citation]

PMID:: 28798025
PMCID:: PMC5665372

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004356969.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant changes 1 nucleotide in exon 9 of the MYH7 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004822528.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (2)

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		2	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848035.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Arg249X variant in MYH7 has been reported in one individual with left ventricular non-compaction (Miszalski-Jamka 2017). It has also been identified in 1/113734 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 407183). This nonsense variant leads to a premature termination codon at position 249, which is predicted to lead to a truncated or absent protein. Although heterozygous loss-of-function (LOF) variants in MYH7 are not believed to be pathogenic for autosomal dominant forms of cardiomyopathy, there is evidence that can they lead to severe and early onset disease when present in trans with a second MYH7 variant (LMM data). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg249X variant is likely pathogenic for cardiomyopathy in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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