NM_000257.4(MYH7):c.5726G>C (p.Arg1909Pro) AND Primary dilated cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 13, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000035980.8

Allele description [Variation Report for NM_000257.4(MYH7):c.5726G>C (p.Arg1909Pro)]

NM_000257.4(MYH7):c.5726G>C (p.Arg1909Pro)

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.5726G>C (p.Arg1909Pro)

Other names:

NM_000257.3(MYH7):c.5726G>C

HGVS:

NC_000014.9:g.23413823C>G
NG_007884.1:g.26839G>C
NM_000257.4:c.5726G>CMANE SELECT
NP_000248.2:p.Arg1909Pro
LRG_384t1:c.5726G>C
LRG_384:g.26839G>C
NC_000014.8:g.23883032C>G
NM_000257.2:c.5726G>C
c.5726G>C

Protein change:

R1909P

Links:

dbSNP: rs397516253

NCBI 1000 Genomes Browser:

rs397516253

Molecular consequence:

NM_000257.4:c.5726G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Primary dilated cardiomyopathy (DCM)
Synonyms:: Dilated Cardiomyopathy
Identifiers:: EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059632	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jan 6, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000564462	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Uncertain significance (Oct 13, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059632

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jan 6, 2014)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000564462

ClinGen Cardiomyopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)

Uncertain significance
(Oct 13, 2021)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	3	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.

Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, Jongbloed JDH, Macaya D, Manrai A, Orland K, Richard G, Spoonamore K, Thomas M, Thomson K, Vincent LM, Walsh R, Watkins H, Whiffin N, et al.

Genet Med. 2018 Mar;20(3):351-359. doi: 10.1038/gim.2017.218. Epub 2018 Jan 4.

PubMed [citation]

PMID:: 29300372
PMCID:: PMC5876064

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059632.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	1	not provided

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000564462.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The c.5726G>C (p.Arg1909Pro) variant in MYH7 has been reported as a de novo occurrence in 1 individual with dilated cardiomyopathy and myopathy features (PM6; Partners LMM ClinVar SCV000059632.5). Additionally, this variant reportedly segregated with DCM and in 2 affected relatives (Partners LMM ClinVar SCV000059632.5); however this data is currently insufficient to establish co-segregation and apply PP1. This variant was absent from large population studies (PM2; https://gnomad.broadinstitute.org, v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). This variant was previously classified as likely pathogenic for DCM by this expert panel (EP) based on clinical judgement; however, upon re-evaluation, the EP has deemed that uncertain significance was more appropriate based on the available evidence. In summary, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM6, PM2, PP3.

#	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: Apr 6, 2024

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