NM_000257.4(MYH7):c.740T>G (p.Phe247Cys) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: May 15, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000507832.4

Allele description [Variation Report for NM_000257.4(MYH7):c.740T>G (p.Phe247Cys)]

NM_000257.4(MYH7):c.740T>G (p.Phe247Cys)

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.740T>G (p.Phe247Cys)
Other names:
p.F247C:TTC>TGC
HGVS:
  • NC_000014.9:g.23431474A>C
  • NG_007884.1:g.9188T>G
  • NM_000257.4:c.740T>GMANE SELECT
  • NP_000248.2:p.Phe247Cys
  • LRG_384t1:c.740T>G
  • LRG_384:g.9188T>G
  • NC_000014.8:g.23900683A>C
  • NM_000257.2:c.740T>G
  • NM_000257.3:c.740T>G
Protein change:
F247C
Links:
dbSNP: rs730880922
NCBI 1000 Genomes Browser:
rs730880922
Molecular consequence:
  • NM_000257.4:c.740T>G - 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
SCV000604367ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(May 15, 2018)
germlineclinical testing

Citation Link,

SCV000731452Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Jan 27, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]
PMID:
27532257
PMCID:
PMC5116235

Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy.

Jordan DM, Kiezun A, Baxter SM, Agarwala V, Green RC, Murray MF, Pugh T, Lebo MS, Rehm HL, Funke BH, Sunyaev SR.

Am J Hum Genet. 2011 Feb 11;88(2):183-92. doi: 10.1016/j.ajhg.2011.01.011.

PubMed [citation]
PMID:
21310275
PMCID:
PMC3035712
See all PubMed Citations (3)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604367.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000731452.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe247Cys variant in MYH7 has not been previously reported in individuals with cardiomyop athy, but has been reported in ClinVar (Variation ID: 181401). This variant was absent from large population studies. Of note, this variant lies in the head reg ion of the protein. Missense variants in this region have been reported and stat istically indicated to be more likely to cause disease (Walsh 2016). Phenylalani ne (Phe) at position 247 is highly conserved in mammals and across evolutionaril y distant species and the change to cysteine (Cys) was predicted to be pathogeni c 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, the clinical s ignificance of the p.Phe247Cys variant is uncertain.

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

Last Updated: Nov 11, 2021

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