NM_000257.4(MYH7):c.715G>A (p.Asp239Asn) AND Hypertrophic cardiomyopathy

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Mar 22, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000628940.16

Allele description [Variation Report for NM_000257.4(MYH7):c.715G>A (p.Asp239Asn)]

NM_000257.4(MYH7):c.715G>A (p.Asp239Asn)

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.715G>A (p.Asp239Asn)

Other names:

NM_000257.4(MYH7):c.715G>A

HGVS:

NC_000014.9:g.23431602C>T
NG_007884.1:g.9060G>A
NM_000257.4:c.715G>AMANE SELECT
NP_000248.2:p.Asp239Asn
LRG_384t1:c.715G>A
LRG_384:g.9060G>A
NC_000014.8:g.23900811C>T
NM_000257.2:c.715G>A
NM_000257.3:c.715G>A
c.715G>A

Protein change:

D239N

Links:

dbSNP: rs397516264

NCBI 1000 Genomes Browser:

rs397516264

Molecular consequence:

NM_000257.4:c.715G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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471011[uid] (1)
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MedGen
C3887496[conceptid] (1)
MedGen
JGI_XZG16614.rev NIH_XGC_tropGas7 Xenopus tropicalis cDNA clone IMAGE:7532691 3'...
JGI_XZG16614.rev NIH_XGC_tropGas7 Xenopus tropicalis cDNA clone IMAGE:7532691 3', mRNA sequence
gi|57249192|gnl|dbEST|27055235|gb|C 72.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059647	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17438619, 20031618, 21896538, 26914223, 27532257, 26743238, 27247418, 27974200, 28615295, 25741868
SCV000212639	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 4, 2019)	germline	research	PubMed (10) [See all records that cite these PMIDs] 17438619, 20031618, 27532257, 21896538, 26743238, 27974200, 28408708, 26914223, 25351510, 25741868
SCV000749848	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 20031618, 21896538, 26743238, 26914223, 27247418, 27974200, 27532257, 28492532
SCV001842656	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Likely pathogenic (Mar 22, 2021)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy.

Ross SB, Bagnall RD, Ingles J, Van Tintelen JP, Semsarian C.

Circ Cardiovasc Genet. 2017 Jun;10(3). doi:pii: e001671. 10.1161/CIRCGENETICS.116.001671.

PubMed [citation]

PMID:: 28615295

Gene symbol: MYH7.

Iascone MR, Marchetti D, Ferrazzi P.

Hum Genet. 2007 Feb;120(6):916. No abstract available.

PubMed [citation]

PMID:: 17438619

See all PubMed Citations (13)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059647.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The p.Asp239Asn variant in MYH7 has been identified in at least 15 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 7 affected relatives (Iascone 2007 PMID: 17438619, Kaski 2009 PMID: 20031618, Garcia-Pavia 2011 PMID: 21896538, Homburger 2016 PMID: 27247418, Adler 2016 PMID: 26743238, Murphy 2016 PMID: 26914223, Walsh 2017 PMID: 27532257, Ross 2017 PMID: 28615295, LMM data). It has also been identified in 1/34592 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.2.1.1). An in vitro functional study supports an impact on protein function (Adhikari 2016 PMID: 27974200). Of note, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID: 27532257). Additionally, this variant was classified as likely pathogenic by the ClinGen-approved cardiomyopathy variant curation expert panel (Variation ID: 43100). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM1, PM2_Supporting, PP1_Strong, PS3_Supporting.

#	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 Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV000212639.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (10)

Description

MYH7 Asp239Asn has been previously reported in multiple HCM cases (Walsh et al., 2017; Adler et al., 2016; Murphy et al., 2016; Garcia-Pavia et al., 2011; Kaski et al., 2009; Iascone et al., 2007) and has been found to segregate in their families (Garcia-Pavia et al., 2011; Ambry, ClinVar SCV000740109.2). We have also identified MYH7 Asp239Asn in a HCM proband (Ingles et al., 2017) as well as their 3 affected family members. This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000004. An in vitro functional study showed that the variant results in higher actin activated ATPase activity, higher actin gliding velocities and increased intrinsic force of the protein which results in hypercontractility (Adhikari et al., 2016). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. In silico tools PolyPhen2 and MutationTaster predict this variant to be deleterious, however SIFT predicts it to be "Tolerated". Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been identified in at least 12 HCM probands without additional variants (PS4_moderate), shown to segregate strongly with disease across multiple families (PP1_Supporting), has been shown to have a damaging affect on protein in a functional study (PS3), it is located in a mutational hotspot (PM1) and is rare in the general population (PM2), therefore we classify MYH7 Asp239Asn as 'pathogenic'.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000749848.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 239 of the MYH7 protein (p.Asp239Asn). This variant is present in population databases (rs397516264, gnomAD 0.003%). This missense change has been observed in individuals with inherited arrhythmia and hypertrophic cardiomyopathy (PMID: 20031618, 21896538, 26743238, 26914223, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 43100). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 27974200). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.

#	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 ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV001842656.1

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

Description

The c.715G>A (p.Asp239Asn) variant in MYH7 has been identified in at least 13 individuals with HCM (PS4_Moderate; Iascone 2007 PMID:17438619; Kaski 2009 PMID:20031618; Garcia-Pavia 2011 PMID:21896538; Murphy 2016 PMID:26914223; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ingles 2017 PMID:28408708) and segregated with HCM in 5 affected individuals from 4 families (PP1_Moderate; Iascone 2007 PMID:17438619; Garcia-Pavia 2011 PMID:21896538; LMM ClinVar SCV000059647.6 and pers comm). This variant has been identified in 0.003% (1/34592) of Latino chromosomes but is absent from all other populations in gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PP1_Moderate; PM2; PM1

#	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

Last Updated: Sep 29, 2024

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