NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Nov 24, 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:: RCV000158512.16

Allele description [Variation Report for NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp)]

NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp)

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.2155C>T (p.Arg719Trp)

Other names:

p.R719W:CGG>TGG; NM_000257.3(MYH7):c.2155C>T

HGVS:

NC_000014.9:g.23425971G>A
NG_007884.1:g.14691C>T
NM_000257.4:c.2155C>TMANE SELECT
NP_000248.2:p.Arg719Trp
LRG_384t1:c.2155C>T
LRG_384:g.14691C>T
NC_000014.8:g.23895180G>A
NM_000257.2:c.2155C>T
NM_000257.3:c.2155C>T
P12883:p.Arg719Trp
c.2155C>T

Protein change:

R719W; ARG719TRP

Links:

UniProtKB: P12883#VAR_004584; OMIM: 160760.0017; dbSNP: rs121913637

NCBI 1000 Genomes Browser:

rs121913637

Molecular consequence:

NM_000257.4:c.2155C>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
SCV000208447	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 24, 2021)	germline	clinical testing	Citation Link,
SCV000226727	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Apr 3, 2015)	germline	clinical testing	Citation Link,
SCV000280311	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Dec 10, 2013)	germline	clinical testing
SCV000927157	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Feb 18, 2017)	germline	clinical testing	Citation Link,
SCV001742585	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001972737	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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	17	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	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

Details of each submission

From GeneDx, SCV000208447.14

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

Description

Not observed at a 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; Published functional studies demonstrate increased myosin activity, reduced calcium sensitivity, and increased muscle fiber stiffness (Kohler et al., 2002; Adhikari et al., 2019); This variant is associated with the following publications: (PMID: 27247418, 16504640, 10882745, 8282798, 28166811, 28138913, 7874131, 29907873, 19651039, 9544842, 9822100, 21769673, 25346696, 20624503, 21310275, 23816408, 27532257, 29300372, 19645038, 27082122, 29497013, 29386531, 28420666, 29101517, 28296734, 24510615, 29029073, 29343710, 11904418, 24829265, 30775854, 31737537, 31213605, 32612965, 33673806, 32746448, 32894683)

#	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 Eurofins Ntd Llc (ga), SCV000226727.5

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280311.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	17	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. This variant has been reported in at least 17 unrelated individuals with HCM (including the two patients in our center) with strong segregation data. Of note, there is data suggesting this variant is associated with a more severe phenotype and high penetrance. In our center we have seen the variant in two patients: a woman diagnosed with HCM at 14 years of age and a man diagnosed with HCM at 29 years of age. The variant was first reported by Greve et al (1994). Unfortunately that report is not available, though the title suggests the variant was de novo. The same group reported four unrelated families with p.Arg719Trp (Anan et al 1994). The authors note that all individuals with HCM in these three kindreds carried the variant. They don’t specify how many individuals were genotyped, though it seems that at least 9 were tested from one family and at least 12 in another, providing very strong segregation data. Jeschke et al (1998) reported a case of childhood-onset HCM and arrest with p.Arg719Trp, which arose de novo, and an additional MYH7 variant inherited from the unaffected mother (p.Met349Thr) (also reported in Dohlemann et al 2000). Paternity was confirmed. While maternity was not formally assesed, it is highly likely to be as reported given maternal inheritance of p.Met349Thr. Jaaskelainen et al (1998) observed the variant in three affected family members from their Finnish cohort. The proband’s mother did have some hypertrophy but was negative for the variant. Poutanen et al (2006) reported two children from the same family with p.Arg719Trp who both had wall thickness at the upper limits of normal, diastolic dysfunction, and pathological Q waves. Richard et al (2003) observed the variant in one individual in their French HCM cohort. Erdmann et al (2003) reported the variant segregating with HCM in two affected members of one family from their German cohort. Frisso et al (2009) observed the variant in three unrelated individuals from their Italian cohort. Santos et al (2012) observed this variant in one individual in their Portuguese cohort. GeneDx reports that p.Arg719Trp was observed in multiple additional unrelated individuals tested for HCM. This is a non-conservative amino acid change with a polar, positive Arginine replaced with a non polar, neutral Tryptophan. Mutationtaster and PolyPhen2 both predict the variant to be damaging. Arginine is conserved at this position across mammals. Other variants at the same codon (p.Arg719Gln (which we consider likely disease causing), p.Arg719Pro) and nearby codons (p.Gly716Arg, p.Arg721Lys, p.Arg712Leu, p.Gly716Arg, p.Arg723Cys, p.Arg723Gly, and p.Ala728Val have been reported in association with HCM (Harvard Sarcomere Protein Gene Mutation Database). Seebohm B et al (2009) demonstrated that the variant could interfere with myosin cross bridge function during contraction. Kohler et al (2002) observed an increase in force generation and fiber stiffness of muscle fibers with p.Arg719Trp and suggested that the cross-bridges were more resistant to elastic distortion. Anan et al (1994) suggested that this variant may be correlated with a particularly severe phenotype since the four families they studied with the variant had a particularly high frequency of disease-related deaths. Many of the initial genotype-phenotype correlations based on a handful of cases have since been called into question by the observation of mild disease in other families with the same variant, suggesting the initial observations may have been due to ascertainment bias. However, a recent paper from the same group found significantly earlier age of onset and age of first cardiac event in carriers of p.Arg719Trp as compared to carriers of MYBPC3 truncating variants or p.Arg502Trp in MYBPC3 (the most prevalent HCM-causing variant) (Saltzman et al 2010). All carriers had manifest disease by 30 years of age. It is unclear though, how many p.Arg719Trp carriers were included or how they were ascertained. Unfortunately many of the case reports reviewed above do not provide detailed data on severity, progression, or outcome. The variant was not observed in ~7000 published controls and publically available general population samples. GeneDx did not report internal control data. The variant is not listed in 1000 Genomes. There is no variation at codon 719 currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on approximately 6500 Caucasian and African American individuals (as of May 2014). Richard et al (2003) did not observe the variant in 100 controls. Frisso et al (2009) did not observe the variant in 200 controls with normal ECGs. Santos et al (2012) did not observe the variant in 100 healthy individuals.

#	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		17	not provided	not provided	not provided

From Blueprint Genetics, SCV000927157.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001742585.3

#	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, SCV001972737.1

#	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

Last Updated: Nov 3, 2024

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