NM_000257.4(MYH7):c.2606G>A (p.Arg869His) AND Primary familial hypertrophic cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 27, 2020
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:: RCV000845415.11

Allele description [Variation Report for NM_000257.4(MYH7):c.2606G>A (p.Arg869His)]

NM_000257.4(MYH7):c.2606G>A (p.Arg869His)

Genes:

LOC126861898:BRD4-independent group 4 enhancer GRCh37_chr14:23893609-23894808 [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.2606G>A (p.Arg869His)

Other names:

NM_000257.4(MYH7):c.2606G>A

HGVS:

NC_000014.9:g.23424842C>T
NG_007884.1:g.15820G>A
NM_000257.4:c.2606G>AMANE SELECT
NP_000248.2:p.Arg869His
LRG_384t1:c.2606G>A
LRG_384:g.15820G>A
NC_000014.8:g.23894051C>T
NM_000257.2:c.2606G>A
NM_000257.3:c.2606G>A
P12883:p.Arg869His

Protein change:

R869H

Links:

UniProtKB: P12883#VAR_042810; dbSNP: rs202141173

NCBI 1000 Genomes Browser:

rs202141173

Molecular consequence:

NM_000257.4:c.2606G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Primary familial hypertrophic cardiomyopathy (HCM)
Synonyms:: Hereditary ventricular hypertrophy; Idiopathic hypertrophic subaortic stenosis
Identifiers:: MONDO: MONDO:0024573; MeSH: D024741; MedGen: C0949658; OMIM: PS192600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696345	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 27, 2019)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 16858239, 15358028, 18533079, 21835320, 22763267, 20359594, 24793961, 25524337, 25078086, 23674513, 27247418, 27532257, 26332594, 29121657, 31112422, 30297972 Citation Link,
SCV000987483	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001147002	Cardiology unit, Meyer University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 27, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696345

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 27, 2019)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

Citation Link,

SCV000987483

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

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

SCV001147002

Cardiology unit, Meyer University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 27, 2020)

germline

clinical testing

Help

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	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
White, European	germline	yes	30	30	not provided	not provided	not provided	clinical testing

Citations

PubMed

A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy.

Girolami F, Olivotto I, Passerini I, Zachara E, Nistri S, Re F, Fantini S, Baldini K, Torricelli F, Cecchi F.

J Cardiovasc Med (Hagerstown). 2006 Aug;7(8):601-7.

PubMed [citation]

PMID:: 16858239

Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.

Van Driest SL, Jaeger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ, Ackerman MJ.

J Am Coll Cardiol. 2004 Aug 4;44(3):602-10.

PubMed [citation]

PMID:: 15358028

See all PubMed Citations (17)

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696345.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

Variant Summary: MYH7 c.2606G>A (p.Arg869His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928). Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3, PP2). The variant allele was found at a frequency of 2.4e-05 in 251440 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2606G>A has been reported in the literature in several well phenotyped individuals affected with and meeting established clinical criteria for Hypertrophic Cardiomyopathy (HCM) (e.g. Witjas-Paalberends_2013, Adalsteinsdottir_2014, Olivotto_2011, Girolami_2010, Walsh_2017, Ho_2018). Though the variant was reported to co-occur with other pathogenic MYBPC3 variants in two different families, the double heterozygous patients showed an earlier onset of HCM, a more rapid disease progression with a more severe phenotype than heterozygous variant carriers, which might be consistent with an additive effect for the co-occurring variants (Girolami_2010, Olivotto_2011). A recent study reported that the allele frequency of this variant in a cohort of HCM patients is much higher (0.0076; i.e. 42/5526 alleles) than that in controls (6/251440 in gnomAD), suggesting this variant could be associated with HCM (Ho_2018) (ACMG PS4). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant: four times as likely pathogenic and once as uncertain significance. In addition, other variants affecting the same codon, R869C, R869G, R869L, have been reported in HGMD in association with HCM (ACMG PM1). Based on the evidence outlined above the variant was re-classified as likely 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 Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000987483.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Cardiology unit, Meyer University Hospital, SCV001147002.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White, European	30	not provided	not provided	clinical testing	not provided

Description

This variant is carried by 30 of 1198 unrelated probands with HCM tested at the Careggi University Hospital as opposed to 0 of 356 non-HCM probands tested in the same lab (p=6.22E-4).

Description

The MYH7:Arg869His variant has been implicated in HCM in several studies (Van Driest et al, 2004; Girolami et al., 2006, Olivotto et al., 2008; Girolami et al., 2010; Witjas-Paalberens et al., 2013; Marsiglia et al., 2013; Adalsteinsdottir et al., 2014; Bos et al., 2014; Mazzarotto & Girolami et al., 2018). This variant is sufficiently rare in the gnomAD population database (MAF 2.39E-5) to activate the PM2 moderate criteria for rarity as per the ACMG/AMP variant interpretation guidelines adapted for MYH7 variants in cardiomyopathy (Kelly et al., 2018). The Arg869His variant alters a residue within the myosin head, which constitutes a large hotspot for variants with a high prior likelihood of pathogenicity in HCM characterised by etiological fraction >0.95 (Kelly et al., 2018 defines ita s between residues 181-937; Walsh et al., 2019 as 167-931), causing the activation of the PM1 criteria (Kelly et al., 2018). Furthermore, we found evidence of co-segregation with HCM in a large Italian pedigree comprising 7 affected carriers and 1 deceased obligate carrier reported to be affected. This enables activation of the PP1_strong criteria for observing >=7 meioses (Kelly et al., 2018). This variant is also carried by 30 of 1198 unrelated probands with HCM tested at the nearby Careggi University Hospital as opposed to 0 of 356 non-HCM probands tested in the same lab (p=6.22E-4), enabling activation of the PS4_strong criteria (Mazzarotto & Girolami et al., 2018; Kelly et al., 2018). Computational evidence is also to be considered supportive of pathogenicity, as multiple in silico pathogenicity predictors classify this variant as damaging / deleterious, enabling activation of the PP3 criteria supporting pathogenicity. In conclusion, the activation of 2 strong, 2 moderate and 1 supporting criteria in favour of pathogenicity enables classification of the MYH7:Arg869His variant as pathogenic for HCM.

#	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		30	not provided	30	not provided

Last Updated: May 12, 2024

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