chr14-23427723-C-G

Position:

• chr14-23427723-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3 PM1 PM2 PP1_Moderate PS4

This summary comes from the ClinGen Evidence Repository: The c.1750G>C (p.Gly584Arg) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:1552912; PMID:10567705; PMID:24093860; Partners LMM ClinVar SCV000059395.5; SHaRe consortium, PMID:30297972). This variant segregated with disease in >5 affected individuals (PP1_Moderate; PMID:1552912; Partners LMM ClinVar SCV000059395.5). This variant was absent from large population studies (PM2; http://exac.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; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011186/MONDO:0005045/002

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 7.60

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.1750G>C	p.Gly584Arg	missense_variant	16/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.1750G>C	p.Gly584Arg	missense_variant	15/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.1750G>C	p.Gly584Arg	missense_variant	16/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2021	Classified in ClinVar as a pathogenic variant by the ClinGen Inherited Cardiomyopathy Expert Panel (ClinVar Variant ID# 14090; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Functional studies demonstrate that this variant causes myofibril disarray in embryonic chicken cardiomyocytes (Wang et al., 2003); 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: 8250038, 7731997, 9062359, 21769673, 23408646, 27639548, 27247418, 1552912, 8335820, 22429680, 24093860, 28606303, 28166811, 21310275, 27532257, 25611685, 28193612, 29300372, 10567705, 30275503, 31447099, 12953063) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 07, 2014	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 c.1750G>C p.Gly584Arg g.23896932C>G (chr14.GRCh37) Seen in 1 pt with HCM in our center. First reviewed 4/1/2013, re-reviewed 1 oct 2014 While the variant has been seen in many cases of cardiomyopathy, we consider it likely pathogenic instead of very likely pathogenic because of the absence of a large number of controls matching the published cases (which are nearly all Portuguese) as well as the lack of strong segregation data or animal model data. In total this variant has been seen in at least 29 unrelated individuals with HCM (including one patient in our center) with weak segregation data in two families. We have seen the variant once in our center, in a Portuguese man who was diagnosed at 58 years of age with HCM, with a septum of 3.1 cm. This variant was initially reported in two families with HCM (Watkins et al 1993). In one family a haplotype block containing the variant segregated with 3 affected individuals, and in the second family it segregated with 2 affecteds. Both families were of Portuguese origin, and they had identical haplotypes thus suggesting p.Gly584Arg is a founder variant in this population. In a study on 80 Portuguese patients with HCM Santos et al (2012) observed the variant in one individual with HCM. Vieira et al (1995) appear to have assessed the prevalence of this variant in a Portuguese population. The manuscript is in Portuguese. Using google translate we were able to ascertain that they did not observe this variant in their cohort, but unfortunately it is unclear how many patients they studied or if they published controls. GeneDx shared that they have seen this variant in two other probands, one Caucasian and the other Portuguese. I also contacted the Laboratory for Molecular Medicine and they shared that they have seen it in 23 cases (2013). Unfortunately they have no segregation data nor do they have detailed ancestry data. They shared that most of the cases were listed as Caucasian without further specifics, though they did notice that many of the patients have Portuguese names. Carolyn Ho’s group included a patient with this variant in a paper on extracellular volume expansion, however it is unclear if that individual had hypertrophy or not (Ho et al 2013). In addition, that case likely overlaps with the LMM’s cases. No ancestry or segregation data was reported. Per their ClinVar submissions, LMM classifies it as likely pathogenic (SCV000059395). This is a semi conservative amino acid change with a nonpolar, neutral Glycine replaced with a polar, positively charged Arginine. In silico analysis (SIFT, PolyPhen2, mutationtaster) predicts the amino acid change to be deleterious/probably damaging to the resulting protein. The Laboratory of Molecular Medicine shared that their sarcomere-specific PolyPhen predicts the variant to be pathogenic and the lab notes that the pathogenic prediction is estimated to be correct 94% of the time (Jordan et al 2011). Additional variants at the same codon (p.Gly584Ser (Erdmann et al 2003, per ClinVar LMM classifies as likely pathogenic (SCV000059394)) and nearby codons (p.His576Arg, p.Ala583Val, p.Asp587Val) have been reported in association with cardiomyopathy (per the GeneDx report citing HGMD). Wang et al (2003) observed dramatic myofibril disarray after introducing the variant into chicken embryonic myocytes. Nier et al (1999) studied muscle fibers from a patient with p.Gly584Arg and observed that only 12% of all myosin in the sarcomeres was the variant version. However they did not observe any impact on sarcomere function. In total the variant has not been seen in ~6600 published controls and publicly available general population samples -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 05, 2024	PP1_moderate, PP3, PM1, PM2, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 28, 2021	- -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 584 of the MYH7 protein (p.Gly584Arg). This variant is present in population databases (rs121913626, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8250038, 22429680, 24093860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14090). 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: 12953063). This variant disrupts the p.Gly584 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12974739, 23283745, 24510615, 26187847). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2021	The p.Gly584Arg variant in MYH7 has been reported in at least 8 individuals with HCM (Watkins 1993 PMID:8250038, Nier 1999 PMID:10567705, Santos 2012 PMID: 22429680, Marsiglia 2013 PMID:24093860) and has been identified by our laboratory in >20 individuals with HCM. Furthermore, this variant segregated with disease in 5 affected members (including 1 obligate carrier) from 4 families (Watkins 1993 PMID:8250038, LMM data). It has also been identified in 0.001% (1/113768) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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). In vitro functional studies support an impact on protein function (Fujita 1998 PMID:9062359, Wang 2003 PMID:12953063) and computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, this variant was classified as pathogenic on 12/15/2016 by the ClinGen-approved Cardiomyopathy expert panel (Variation ID 14090). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Moderate, PM2_supporting, PM1, PS3_Supporting, PP3. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.1750G>C (p.Gly584Arg) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:1552912; PMID:10567705; PMID:24093860; Partners LMM ClinVar SCV000059395.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >5 affected individuals (PP1_Moderate; PMID:1552912; Partners LMM ClinVar SCV000059395.5). This variant was absent from large population studies (PM2; http://exac.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; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate; PP3 -

Hypertrophic cardiomyopathy 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 23, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 05, 2022

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Oct 24, 2016

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2021

The p.G584R pathogenic mutation (also known as c.1750G>C), located in coding exon 14 of the MYH7 gene, results from a G to C substitution at nucleotide position 1750. The glycine at codon 584 is replaced by arginine, an amino acid with dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM), with segregation reported in affected relatives from at least two families (Solomon SD et al. J. Am. Coll. Cardiol., 1993 Aug;22:498-505; Watkins H et al. Am. J. Hum. Genet., 1993 Dec;53:1180-5; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Walsh R et al. Genet. Med., 2017 02;19:192-203). Functional studies have suggested that this alteration leads to impaired function and increased myofibril disarray (Fujita H et al. J. Clin. Invest., 1997 Mar;99:1010-5; Wang Q et al. J. Cell. Sci., 2003 Oct;116:4227-38). An alternate amino acid substitution at this position, p.G584S (c.1750G>A) has also been reported in multiple patients with HCM (Erdmann J et al. Clin Genet. 2003;64(4):339-49). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.78		Gain of catalytic residue at N589 (P = 8e-04);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.80
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121913626; hg19: chr14-23896932;