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NM_000257.4(MYH7):c.5302G>A (p.Glu1768Lys) AND not specified

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jun 5, 2014
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000035954.7

Allele description [Variation Report for NM_000257.4(MYH7):c.5302G>A (p.Glu1768Lys)]

NM_000257.4(MYH7):c.5302G>A (p.Glu1768Lys)

Genes:
LOC126861897:BRD4-independent group 4 enhancer GRCh37_chr14:23884455-23885654 [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.5302G>A (p.Glu1768Lys)
Other names:
NM_000257.3(MYH7):c.5302G>A
HGVS:
  • NC_000014.9:g.23415252C>T
  • NG_007884.1:g.25410G>A
  • NM_000257.4:c.5302G>AMANE SELECT
  • NP_000248.2:p.Glu1768Lys
  • LRG_384t1:c.5302G>A
  • LRG_384:g.25410G>A
  • NC_000014.8:g.23884461C>T
  • NM_000257.2:c.5302G>A
  • NM_000257.3:c.5302G>A
  • P12883:p.Glu1768Lys
  • c.5302G>A
Protein change:
E1768K
Links:
UniProtKB: P12883#VAR_042837; dbSNP: rs397516241
NCBI 1000 Genomes Browser:
rs397516241
Molecular consequence:
  • NM_000257.4:c.5302G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000059606Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Uncertain significance
(Jun 5, 2014)
germlineclinical testing

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

SCV000280362Stanford Center for Inherited Cardiovascular Disease, Stanford University
no assertion criteria provided
Uncertain significance
(Dec 9, 2013)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided61not providednot providednot providedclinical testing

Citations

PubMed

Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.

Van Driest SL, Jaeger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ, Ackerman MJ.

J Am Coll Cardiol. 2004 Aug 4;44(3):602-10.

PubMed [citation]
PMID:
15358028

Cardiomyopathy mutations in the tail of β-cardiac myosin modify the coiled-coil structure and affect integration into thick filaments in muscle sarcomeres in adult cardiomyocytes.

Wolny M, Colegrave M, Colman L, White E, Knight PJ, Peckham M.

J Biol Chem. 2013 Nov 1;288(44):31952-62. doi: 10.1074/jbc.M113.513291. Epub 2013 Sep 18. Erratum in: J Biol Chem. 2013 Dec 20;288(51):36260.

PubMed [citation]
PMID:
24047955
PMCID:
PMC3814791
See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059606.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (3)

Description

Variant classified as Uncertain Significance - Favor Pathogenic. The Glu1768Lys variant in MYH7 has been reported in 1 individual with HCM (Van Driest 2004) and has also been identified by our laboratory in 1 Caucasian individual with HCM a nd in 1 affected relative with syncope. It was absent from large population stud ies. Glutamic acid (Glu) at position 1768 is highly conserved in mammals and acr oss evolutionarily distant species and the change to lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by our laborato ry. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role of this variant in disease, the clinical significance is uncertain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided1not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280362.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu1768Lys, E1768K, (c.5302G>A) in the MYH7 gene. We had initially classified this variant as likely disease causing, however, given the weak case data and the lack of Asian controls, we reclassified it to variant of uncertain significance, probably disease causing in 2014. We now have Asian frequency data from ExAC showing it is rare in that population. Thus we are increasingly feel it is more likely that this variant is in fact disease causing, however it remains classified as a variant of uncertain significance, probably disease. An additional case would probably shift it to likely disease causing. The variant has been seen in at least three patients and possibly as many as five presumably unrelated patients with HCM, not including this patient. Van Driest et al., 2004 reported the variant in a cohort of 350 individuals with HCM, with no specific case data available for this variant, including ancestry data. Bos et al (2014) reported the variant in two patients with HCM in their Mayo cohort who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases may overlap with prior reports by Ackerman's group (ex. van Driest et al 2004) and with the clinical labs since some of these patients likely underwent clinical genetic testing. These two cases also likely overlap with two of the three reported by Kapplinger et al (2014) since that dataset includes Mayo cases and patients referred to Transgenomic for genetic testing. Unfortunately phenotypic data is not provided and so we cannot confirm if cases tested at Transgenomic had HCM. This variant has also been seen in another individual in our center with HCM, also of Asian ancestry. LMM's ClinVar assertion is "uncertain significance", with the following data: "The Glu1768Lys variant in MYH7 has been reported in 1 individual with HCM (Van Driest 2004) and has also been identified by our laboratory in 1 Caucasian individual with HCM and in 1 affected relative with syncope. It was absent from large population studies. Glutamic acid (Glu) at position 1768 is highly conserved in mammals and across evolutionarily distant species and the change to lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role of this variant in disease, the clinical significance is uncertain." This variant is in the rod portion of MYH7 (exons 24-40) No segregation data is available. This variant changes a polar, acidic glutamic acid to a polar basic lysine. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts it to be disease causing. The glutamic acid at codon 1768 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with cardiomyopathy at nearby codons (Leu1769Met, Klassen et al 2008; Ala1766Thr, Girolamni et al 2006). The variant was reported online in 1 of 60,705 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 24th, 2015). The phenotype of that individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was not observed in the following laboratory and published control samples: GeneDx reports it was not seen in 304 control individuals, Van Driest et al. reports it was not seen in 400 control alleles.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided4not providednot providednot provided

Last Updated: Feb 20, 2024