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NM_000257.4(MYH7):c.550A>C (p.Lys184Gln) AND Hypertrophic cardiomyopathy

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Dec 1, 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:
RCV000818270.6

Allele description [Variation Report for NM_000257.4(MYH7):c.550A>C (p.Lys184Gln)]

NM_000257.4(MYH7):c.550A>C (p.Lys184Gln)

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.550A>C (p.Lys184Gln)
Other names:
p.K184Q:AAG>CAG; NM_000257.4(MYH7):c.550A>C; p.Lys184Gln
HGVS:
  • NC_000014.9:g.23431850T>G
  • NG_007884.1:g.8812A>C
  • NM_000257.4:c.550A>CMANE SELECT
  • NP_000248.2:p.Lys184Gln
  • LRG_384t1:c.550A>C
  • LRG_384:g.8812A>C
  • NC_000014.8:g.23901059T>G
  • NC_000014.8:g.23901059T>G
  • NM_000257.2:c.550A>C
  • NM_000257.3:c.550A>C
Protein change:
K184Q
Links:
dbSNP: rs730880843
NCBI 1000 Genomes Browser:
rs730880843
Molecular consequence:
  • NM_000257.4:c.550A>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000958872Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jul 25, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002041480ClinGen Cardiomyopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)
Uncertain significance
(Dec 1, 2021)
germlinecuration

Citation Link

Summary from all submissions

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

Citations

PubMed

Genetic Testing in Pediatric Left Ventricular Noncompaction.

Miller EM, Hinton RB, Czosek R, Lorts A, Parrott A, Shikany AR, Ittenbach RF, Ware SM.

Circ Cardiovasc Genet. 2017 Dec;10(6). doi:pii: e001735. 10.1161/CIRCGENETICS.117.001735.

PubMed [citation]
PMID:
29212898
PMCID:
PMC8428628

Prevalence and potential genetic determinants of young sudden unexplained death victims with suspected arrhythmogenic mitral valve prolapse syndrome.

Giudicessi JR, Maleszewski JJ, Tester DJ, Ackerman MJ.

Heart Rhythm O2. 2021 Oct;2(5):431-438. doi: 10.1016/j.hroo.2021.07.006.

PubMed [citation]
PMID:
34667957
PMCID:
PMC8505213
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000958872.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 181312). This missense change has been observed in individual(s) with left ventricular noncompaction and/or sudden unexplained death (PMID: 29212898, 34667957). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 184 of the MYH7 protein (p.Lys184Gln).

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

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV002041480.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000257.4(MYH7):c.550A>C (p.Lys184Gln) variant has been identified in at least 4 individuals with LVNC (Miller 2017 PMID:29212898; GeneDx pers. comm.; Invitae pers. comm.), 1 individual with HCM and LVNC (Ambry pers. comm.), 1 individual with HCM who carried another pathogenic variant in MYH7 (GeneDx pers. comm.) and 1 individual with sudden cardiac death. Additionally, this variant has segregated with LVNC in 6 affected relatives from 2 families (GeneDx pers. comm.). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. Therefore, the current evidence is currently insufficient to apply the PS4 or the PP1 criteria for the HCM phenotypes. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM, but location in this region cannot be used to support pathogenicity for other phenotypes ( Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2, PP3.

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

Last Updated: Sep 29, 2024