NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Aug 16, 2022
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:: RCV000158799.16

Allele description [Variation Report for NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys)]

NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys)

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.1357C>T (p.Arg453Cys)

Other names:

p.R453C:CGC>TGC; NM_000257.3(MYH7):c.1357C>T

HGVS:

NC_000014.9:g.23429005G>A
NG_007884.1:g.11657C>T
NM_000257.4:c.1357C>TMANE SELECT
NP_000248.2:p.Arg453Cys
LRG_384t1:c.1357C>T
LRG_384:g.11657C>T
NC_000014.8:g.23898214G>A
NM_000257.2:c.1357C>T
NM_000257.3:c.1357C>T
P12883:p.Arg453Cys
c.1357C>T

Protein change:

R453C; ARG453CYS

Links:

UniProtKB: P12883#VAR_004576; OMIM: 160760.0003; dbSNP: rs121913625

NCBI 1000 Genomes Browser:

rs121913625

Molecular consequence:

NM_000257.4:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000208734	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 1, 2022)	germline	clinical testing	Citation Link,
SCV000280298	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Jan 31, 2012)	germline	clinical testing
SCV001923921	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001930987	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001954721	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001968729	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002017671	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002502849	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 28, 2021)	germline	clinical testing	PubMed (22) [See all records that cite these PMIDs] 1552912, 24344137, 17351073, 10662815, 32013205, 29907873, 27247418, 21310275, 29300372, 27373729, 31006259, 15001446, 31513939, 32283115, 29029073, 23798412, 18365899, 23349452, 27532257, 9541100, 23283745, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	10	not provided	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

Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy.

Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, Seidman JG.

N Engl J Med. 1992 Apr 23;326(17):1108-14.

PubMed [citation]

PMID:: 1552912

The hypertrophic cardiomyopathy myosin mutation R453C alters ATP binding and hydrolysis of human cardiac β-myosin.

Bloemink M, Deacon J, Langer S, Vera C, Combs A, Leinwand L, Geeves MA.

J Biol Chem. 2014 Feb 21;289(8):5158-67. doi: 10.1074/jbc.M113.511204. Epub 2013 Dec 16.

PubMed [citation]

PMID:: 24344137
PMCID:: PMC3931073

See all PubMed Citations (22)

Details of each submission

From GeneDx, SCV000208734.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as reduced ATPase activity and enhanced calcium sensitivity result in a hyper-contractile state of the cardiac muscle (Palmer et al., 2004; Debold et al., 2007; Tajsharghi et al., 2008; Sommese et al., 2013; Bloemink et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified in ClinVar as a pathogenic variant by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564414.4; ClinVar); This variant is associated with the following publications: (PMID: 17351073, 17495353, 15851227, 17599605, 16715312, 18175163, 12707239, 29029073, 1552912, 23283745, 12881443, 15358028, 23349452, 12951062, 15856146, 18365899, 15001446, 23798412, 10662815, 11133230, 27247418, 21310275, 27373729, 27532257, 9541100, 1739523, 24111713, 29300372, 8655135, 12975413, 29907873, 31513939, 32013205, 32283115, 24344137, 31006259, 33673806, 33586461)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280298.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	not 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.Arg453Cys (c.1357 C>T) in MYH7 (NM_000257.2) Given the strong case data, segregation data, and mouse model, we consider this variant very likely disease causing. The variant has been seen in over 15 unrelated cases of HCM with strong segregation data. Watkins et al (1992) reported p.Arg453Cys in two families with HCM with a Lod score of 4.4 in one family and a Lod score of 3.9 in the other. Unfortunately details on the number of affected individuals with the variant in each family was not reported. The same authors then reported a third family with HCM and this variant (Watkins et al 1993). In that paper they demonstrated that the variant occurred on three distinct haplotypes in these three families. Ko et al (1996) reported a Chinese kindred with 8 individuals with HCM and p.Arg453Cys. Forissier et al (2000) reported two siblings with HCM and p.Arg453Cys. Interestingly, this was the first reported case of germline mosaicism in HCM. In a cohort of Australian families with HCM, Greber-Platzer et al (2001) reported one family with two affected individuals with p.Arg453Cys. Ackerman et al (2002) reported a child with HCM and p.Arg453Cys. Richard et al (2003) observed p.Arg453Cys in two unrelated individuals with HCM. In a Spanish cohort, Garcia-Castro et al (2003) observed the variant in one case of HCM. Nanni et al (2003) also observed the variant in one individual with HCM. Woo et al (2003) reported two individuals with this variant and HCM (unclear if they are related to each other). Perrot et al (2005) observed the variant in one individual with HCM. Yu et al (2005) observed the variant in one patient with HCM. The variant has been seen with another variant in at least one case (van Driest et al 2004). The patient also carried p.Gln191del in TNNT2. There are multiple additional reports on the variant that I did not review (including, but not limited to Kubo et al 2007, Solomon et al 1993, Bos et al 2014, Kassem et al 2013). We have seen the variant in one other patient with HCM in our center. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 453 is conserved across species, as are neighboring variants. This is a non-conservative amino acid change. There are other variants at this codon: p.Arg453Leu, which we consider a variant of uncertain significance; p.Arg453His, which we consider likely disease causing; p.Arg453Ser, which we have not reviewed. Variants at nearby codons have been reported in association with cardiomyopathy (p.Lys450Glu, p.Lys450Thr). The Seidman group has developed a mouse model with p.Arg453Cys that recapitulates an HCM phenotype (Palmer et al 2004, Debold et al 2007). Some authors have suggested that this variant is associated with a particularly severe phenotype. However, many such assertions made in early studies of HCM genetics were later called in to question when milder cases with such "severe" variants were reported and vice versa (ex. van Driest et al 2002). It is certainly possible that this variant causes a more severe phenotype, however further studies are needed to assess that. In addition, even with such a correlation, there may still be some variability among patients with this variant. In total the variant has not been seen in ~7002 published controls and publicly available population datasets. There is no variation at codon 453 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 15th, 2014). The variant was not observed in published controls: 100 (Richard et al 2003), 100 (Garcia-Castro et al 2003), 100 (Nanni et al 2003), 106 (Woo et al 2003), 96 (Perrot et al 2005). The early publications this variant did not report control data. There may be additional control data in the papers we did not review (see references for some of these above).

#	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		10	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001923921.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001930987.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968729.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002017671.3

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

#	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

From AiLife Diagnostics, AiLife Diagnostics, SCV002502849.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (22)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

Relating variation to medicine