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NM_000257.4(MYH7):c.3134G>T (p.Arg1045Leu) AND Hypertrophic cardiomyopathy

Germline classification:
Likely pathogenic (3 submissions)
Last evaluated:
Aug 25, 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:
RCV000629019.20

Allele description [Variation Report for NM_000257.4(MYH7):c.3134G>T (p.Arg1045Leu)]

NM_000257.4(MYH7):c.3134G>T (p.Arg1045Leu)

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.3134G>T (p.Arg1045Leu)
Other names:
NM_000257.4(MYH7):c.3134G>T
HGVS:
  • NC_000014.9:g.23422291C>A
  • NG_007884.1:g.18371G>T
  • NM_000257.4:c.3134G>TMANE SELECT
  • NP_000248.2:p.Arg1045Leu
  • LRG_384t1:c.3134G>T
  • LRG_384:g.18371G>T
  • NC_000014.8:g.23891500C>A
  • NM_000257.2:c.3134G>T
  • NM_000257.3:c.3134G>T
  • c.3134G>T
Protein change:
R1045L
Links:
dbSNP: rs397516178
NCBI 1000 Genomes Browser:
rs397516178
Molecular consequence:
  • NM_000257.4:c.3134G>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Hypertrophic cardiomyopathy
Synonyms:
HYPERTROPHIC MYOCARDIOPATHY
Identifiers:
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000059492Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Likely pathogenic
(Dec 18, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000749929Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 31, 2023)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001976477ClinGen Cardiomyopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)
Likely pathogenic
(Aug 25, 2021)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown42not providednot providednot providedclinical testing, curation

Citations

PubMed

A child cohort study from southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy.

Frisso G, Limongelli G, Pacileo G, Del Giudice A, Forgione L, CalabrĂ² P, Iacomino M, Detta N, Di Fonzo LM, Maddaloni V, CalabrĂ² R, Salvatore F.

Clin Genet. 2009 Jul;76(1):91-101. doi: 10.1111/j.1399-0004.2009.01190.x.

PubMed [citation]
PMID:
19659763

Phenotype-driven molecular autopsy for sudden cardiac death.

Cann F, Corbett M, O'Sullivan D, Tennant S, Hailey H, Grieve JH, Broadhurst P, Rankin R, Dean JC.

Clin Genet. 2017 Jan;91(1):22-29. doi: 10.1111/cge.12778. Epub 2016 May 11.

PubMed [citation]
PMID:
27000522
See all PubMed Citations (10)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059492.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (6)

Description

The p.Arg1045Leu variant in MYH7 has been identified in at least 11 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 affected relatives from 3 families (Cann 2017, Walsh 2017, Invitae pers. comm., GeneDx pers. comm., LMM data). It has also been identified in 1 individual with HCM who carried an additional pathogenic variant in MYH7 (LMM data). This variant has also reported by other clinical laboratories in ClinVar (Variation ID#42948) and has been identified in 0.004% (4/113744) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg1045Cys) has been identified in individuals with HCM and is classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2, PP1, PP3, PS4_Moderate, PM5_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided4not provided2not provided

From Invitae, SCV000749929.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1045 of the MYH7 protein (p.Arg1045Leu). This variant is present in population databases (rs397516178, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42948). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1045 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 20215591, 24793961, 26914223, 27247418, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV001976477.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.3134G>T (p.Arg1045Leu) variant in MYH7 has been reported in at least 15 individuals with HCM (PS4_Moderate; Cann 2017 PMID:27000522; Sheikh 2018 PMID:29764897, Walsh 2017 PMID:27532257; GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.), 4 of whom also had additional variants in other HCM-associated genes (GeneDx pers. comm., Invitae pers. comm., LMM pers. comm.). Because of the additional variants observed in multiple cases, PS4 was downgraded to Moderate. This variant also segregated with HCM in 6 affected relatives from 3 families (PP1_Moderate; Cann 2017 PMID:27000522; GeneDx pers. comm., LMM pers. comm., OMGL pers. comm.). This variant has also been identified in 0.001% (FAF 95% CI, 4/113744) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PP1_Moderate; PM2; PP3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 23, 2024