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NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp) AND not provided

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Aug 13, 2021
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:
RCV000158523.12

Allele description [Variation Report for NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp)]

NM_000257.4(MYH7):c.2221G>T (p.Gly741Trp)

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.2221G>T (p.Gly741Trp)
Other names:
p.G741W:GGG>TGG; NM_000257.3(MYH7):c.2221G>T
HGVS:
  • NC_000014.9:g.23425760C>A
  • NG_007884.1:g.14902G>T
  • NM_000257.4:c.2221G>TMANE SELECT
  • NP_000248.2:p.Gly741Trp
  • LRG_384t1:c.2221G>T
  • LRG_384:g.14902G>T
  • NC_000014.8:g.23894969C>A
  • NM_000257.2:c.2221G>T
  • NM_000257.3:c.2221G>T
  • P12883:p.Gly741Trp
Protein change:
G741W
Links:
UniProtKB: P12883#VAR_004589; dbSNP: rs121913632
NCBI 1000 Genomes Browser:
rs121913632
Molecular consequence:
  • NM_000257.4:c.2221G>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
9

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000208458GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Aug 13, 2021)
germlineclinical testing

Citation Link,

SCV000226869Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL Classification Definitions 2015)
Pathogenic
(Jan 15, 2015)
germlineclinical testing

Citation Link,

SCV000280319Stanford Center for Inherited Cardiovascular Disease, Stanford University
no assertion criteria provided
Likely pathogenic
(Sep 9, 2015)
germlineclinical testing

SCV001433190Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 7, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided9not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From GeneDx, SCV000208458.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Identified in a multiple patients with HCM referred for genetic testing at GeneDx and in published literature (Arai et al., 1995; Perrot et al., 2005; Pan et al., 2012; Zou et al., 2013; Kapplinger et al., 2014; Walsh et al., 2017; Bagnall et al., 2018); Reported in ClinVar as pathogenic by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564428.2; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31006259, 29907873, 29300372, 27532257, 32344918, 31737537, 29369293, 28166811, 30025578, 28606303, 24810389, 24510615, 23283745, 15856146, 23074333, 21310275, 27247418, 25935763, 26914223, 8533830)

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

From Eurofins Ntd Llc (ga), SCV000226869.5

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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280319.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided9not 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. MYH7 p.Gly741Trp (c.2221G>T) The variant has been seen in at least 9 unrelated individuals with HCM with moderately segregation data in one family. Arai et al (1995) reported a Japanese family with four individuals who all had HCM and carried p.Gly741Trp. The authors of that paper refer to an additional Japanese case, reported in a book chapter by Kimura et al (1994). Perrot et al (2005) reported two siblings from a German family who both had HCM and this variant. Santos et al (2012) observed the variant in one of 80 Portuguese patients with HCM. Ackerman's group observed the variant in 4 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). It is not currently listed in ClinVar (as of October 3rd 2014). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging and mutationtaster predicts it to be disease causing. The glycine at codon 741 is conserved across species, as are neighboring amino acids. Two other variants at the same codon have been associated with cardiomyopathy: p.Gly741Arg (Van Driest et al 2004, we consider this variant very likely disease causing), p.Gly741Ala (primary data unavailable). Variants at nearby codons have also been reported in association with cardiomyopathy (p.Ile736Val, p.Ile736Thr, p.Ile736Met, p.Ala742Glu, p.Glu743Asp). Functional studies have shown that another variant at this codon, p.Gly741Arg, confers reduced isometric force generation and decreased velocity of shortening (Lankford et al 1995). In total the variant has not been seen in ~6896 published controls and publicly available population datasets. There is no variation at codon 741 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of 1 Oct 2014). The variant is listed in dbSNP (rs121913632), however the only submissions are OMIM and LMM (as of 1 October 2014). The variant is not listed in the 1000 genomes dataset (as of 1 October 2014). The variant was not observed in the following published control samples: 96 (Perrot et al 2005), 100 (Santos et al 2012), 200 (Bos et al 2014).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided9not providednot providednot provided

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV001433190.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024