NM_000257.4(MYH7):c.2644C>G (p.Gln882Glu) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000628861.9

Allele description [Variation Report for NM_000257.4(MYH7):c.2644C>G (p.Gln882Glu)]

NM_000257.4(MYH7):c.2644C>G (p.Gln882Glu)

Genes:

LOC126861898:BRD4-independent group 4 enhancer GRCh37_chr14:23893609-23894808 [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.2644C>G (p.Gln882Glu)

HGVS:

NC_000014.9:g.23424804G>C
NG_007884.1:g.15858C>G
NM_000257.4:c.2644C>GMANE SELECT
NP_000248.2:p.Gln882Glu
LRG_384t1:c.2644C>G
LRG_384:g.15858C>G
NC_000014.8:g.23894013G>C
NM_000257.2:c.2644C>G
NM_000257.3:c.2644C>G
P12883:p.Gln882Glu
c.2644C>G

Protein change:

Q882E

Links:

UniProtKB: P12883#VAR_042811; dbSNP: rs397516160

NCBI 1000 Genomes Browser:

rs397516160

Molecular consequence:

NM_000257.4:c.2644C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059462	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Sep 21, 2015)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12820698, 8533830, 22429680, 24033266
SCV000749769	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12820698, 22429680, 27247418, 27532257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059462

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Sep 21, 2015)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000749769

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 6, 2023)

germline

clinical testing

PubMed (5)
[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	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	clinical testing

Citations

PubMed

Missense mutation of the beta-cardiac myosin heavy-chain gene in hypertrophic cardiomyopathy.

Arai S, Matsuoka R, Hirayama K, Sakurai H, Tamura M, Ozawa T, Kimura M, Imamura S, Furutani Y, Joh-o K, et al.

Am J Med Genet. 1995 Sep 11;58(3):267-76.

PubMed [citation]

PMID:: 8533830

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

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059462.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Gln882Glu variant in MYH7 has been reported in 3 individuals with HCM, two of whom also carried a second likely disease-causing variant (Mohiddin 2003, Sa ntos 2012). Our laboratory has identified this variant in 1 individual with HCM and it segregated with disease in 5 affected relatives, including 2 obligate car riers. This variant was absent from large population studies. Computational pred iction tools and conservation analysis suggest that the p.Gln882Glu variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In summary, although additional studies are required to fully e stablish its clinical significance, the p.Gln882Glu variant is likely pathogenic .

#	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 Invitae, SCV000749769.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 882 of the MYH7 protein (p.Gln882Glu). This variant is present in population databases (rs397516160, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12820698, 22429680, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 42921). 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. For these reasons, this variant has been classified as Pathogenic.

#	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 1, 2024

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