rs138049878

chr14-23424840-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000257.4(MYH7):c.2608C>T(p.Arg870Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R870H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:13 U:1
• Conservation: PhyloP100: 1.14

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 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000257.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23424839-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14120.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 14-23424840-G-A is Pathogenic according to our data. Variant chr14-23424840-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161326.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23424840-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2608C>T	p.Arg870Cys	missense_variant	22/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2608C>T	p.Arg870Cys	missense_variant	21/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2608C>T	p.Arg870Cys	missense_variant	22/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251444 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 13, 2022	This MYH7 variant (rs138049878) is rare (<0.1%) in a large population dataset (gnomAD: 6/251444 total alleles, 0.0024%, no homozygotes) and has been reported in ClinVar. This variant has previously been reported in unrelated individuals with CMH1 and was classified by the ClinGen Inherited Cardiomyopathy Expert Panel. 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 associated with CMH1. Additionally, a different pathogenic missense variant, c.2609G>A (p.Arg870His), has been previously identified at this codon which indicates that this residue may be critical to the function of the protein. Two bioinformatic tools queried8 predict that this substitution would be damaging, and the arginine residue at this position is strongly conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 22 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.2608C>T to be likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000161326, 3billion dataset, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014120, PM5_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.8, 3CNET: 0.963, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, no assertion criteria provided	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Sep 22, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 14, 2023	- -

Hypertrophic cardiomyopathy Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Nov 30, 2021	The NM_000257.4(MYH7):c.2608C>T (p.Arg870Cys) variant has been reported in >15 individuals with HCM (PS4; Anan 2000 PMID:10862102; Woo 2003 PMID:12975413; Uchiyama 2009 PMID:19149795; Funada 2010 PMID:20975235; Otsuka 2012 PMID:22112859; Fujita 2013 PMID: 24621997; Wang 2014 PMID:25132132; Mademont-Soler 2017 PMID:28771489; Hayashi 2018 PMID:29907873; Mak 2018 PMID:30022097; Inagaki 2018 PMID:30206291; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with disease in 2 affected individual with HCM from 2 families (Otsuka 2011 PMID 22112859; LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was identified in 0.0007% (FAF 95% CI; 3/113730) of European chromosomes in gnomAD v2.1.1 (PM2; https://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 associated with HCM (Walsh 2017 PMID:27532257). Additionally, a different pathogenic missense variant has been previously identified at this codon which indicates that this residue may be critical to the function of the protein (PM5; NM_000257.4(MYH7):c.2609G>A (p.Arg870His) - Variation ID 14120). 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PM2, PM5, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Arg870Cys variant in MYH7 has been reported in at least 10 individuals with HCM (Anan 2000 PMID:10862102; Woo 2003 PMID:12975413; Uchiyama 2009 PMID:19149795; Funada 2010 PMID:20975235; Otsuka 2012 PMID:22112859; Fujita 2013 PMID: 24621997; Wang 2014 PMID:25132132; Mademont-Soler 2017 PMID:28771489; Hayashi 2018 PMID:29907873; Mak 2018 PMID:30022097; Inagaki 2018 PMID:30206291 LMM data) and segregated with disease in at least 2 affected relatives from 2 families (Otsuka 2012, LMM data). This variant has been identified in 6/251444 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and was classified as likely pathogenic by the ClinGen Inherited Cardiomyopathy Expert Panel on 12/15/16 (Variation ID# 161326). Computational prediction tools and conservation analysis suggest that the p.Arg870Cys variant may impact the protein, and another variant at the same codon (p.Arg870His) is classified as pathogenic variant by our laboratory. In addition, 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 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PM5, PS4_Moderate, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 870 of the MYH7 protein (p.Arg870Cys). This variant is present in population databases (rs138049878, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10862102, 12975413, 20975235, 22112859, 25132132, 27532257, 28771489, 30022097, 30206291). ClinVar contains an entry for this variant (Variation ID: 161326). 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%. This variant disrupts the p.Arg870 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7796500, 9172070, 12974739, 17192269, 17703256). 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. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as likely pathogenic by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (ClinVar Variant ID# 161326); This variant is associated with the following publications: (PMID: 23447461, 27532257, 30022097, 23299917, 25637381, 25892673, 10862102, 12975413, 27247418, 20075948, 20975235, 25611685, 29300372, 30217213, 32286303, 36005429, 31447099, 32492895, 33407484, 33087929, 34542152, 34057638, 35456187, 29907873, 24621997, 22112859, 34428338, 36618848, 30206291, Kawano2021[CaseReport]) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 23, 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. Arg870Cys has been previously observed in association with hypertrophic cardiomyopathy (HCM) in at least 5 unrelated individuals, apparently with good segregation data in one family. Anan et al. (2000) found Arg870Cys in a 61-year-old man of Japanese descent with asymmetrical septal hypertrophy. It appears to have segregated with disease in 5 of his affected family members, but the language of the report is vague (“5 individuals in this family were affected with the mutation.”) The Seidman’s Harvard Sarcomere Protein Gene Mutation Database reports the variant in a male HCM patient with onset at age 13. Woo et al. (2003) found the variant in a Toronto proband with HCM and a family history of 4 other affecteds including 3 premature sudden deaths under the age of 60. Average age at diagnosis for this family was 45 years. No segregation data in affected family members was provided, although several unaffecteds were tested. Arg870Cys has also been observed in two other unrelated individuals tested for HCM at GeneDx, according to the report. Variation at this same locus has been associated with disease, most notably Arg870His which we categorize as very likely diseae causing. The Arg870His variant has been reported in at least 11 unrelated cases of HCM with strong segregation data in one SE-Asian Indian family (11 individuals), good segregation data in 2 additional families, and weak segregation data in two more. Structural and functional data are available. In total it had not been seen in ~5670 published controls and publicly available population datasets as of 1/15/2012. It is present in dbSNP as rs36211715 (“probable-pathogenic”), submitted by the Dept. of Genetics at Osmania University, and also by the OMIM staff at Johns Hopkins. Another variant at this site, Arg870Leu, was reported by the Harvard Sarcomere Protein Gene Mutation Database as a novel variant observed by the Seidman group in two members of one family who both had HCM. Variation at nearby codons of MYH7 (within 10 amino acids to either side) has also been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Ser866Tyr, Ala868Pro, Arg869Cys, Arg869Gly, Arg869His, and Met877Lys (Harvard Sarcomere Protein Gene Mutation Database; Human Gene Mutation Database as reported by GeneDx). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a neutral, polar Cysteine. The Arginine at codon 870 is highly conserved across 40 vertebrate species examined (it is a lysine in 2 species: Stickleback and Tetraodon). Surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” and SIFT predicts it to be “deleterious”. This variant is in the rod domain of the beta-myosin heavy chain protein (Rayment et al. 1995) localized to the coiled-coil alpha-helical S-2 region (Cuda et al. 1997). In total the Arg870Cys variant been seen in 1 out of ~6850 individuals from published controls and publicly available population datasets. It is present in 1/4300 Caucasian individuals and 0/2200 African American individuals in the NHLBI Exome Sequencing Project dataset (as of 11/16/2012). It is listed in dbSNP as rs138049878, and was submitted by NHLBI-ESP. It is not present in 1000 genomes (as of 11/16/2012). Anan et al. (2000) did not find it in at least 50 control individuals of unspecified ancestry, who were likely Japanese to match the affecteds. Woo et al. (2003) did not find it in 106 control individuals. It was not present in up to 200 control individuals of Caucasian and African-Ameri -

Primary familial hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2021	Variant summary: MYH7 c.2608C>T (p.Arg870Cys) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 252156 control chromosomes. This variant occurs in the region enriched for HCM mutations (residues 181-937, Walsh_2017). c.2608C>T has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Woo_2003, Anan_2000, Otsuka_2012, Wang_2014, Mak_2018, Inagaki_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=5) citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 16, 2023

This missense variant replaces arginine with cysteine at codon 870 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 10862102, 12975413, 20975235, 22112859, 24621997, 27532257, 28771489, 29907873, 30022097, 32492895, 33407484, 33495596, 33495597). It has also been reported in an individual affected with restrictive cardiomyopathy (PMID: 29907873) and in an individual affected with neurally mediated syncope (PMID: 36005429). This variant has been identified in 6/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg870His, is considered to be disease-causing (ClinVar variation ID: 14120), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 04, 2021

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2023

The p.R870C variant (also known as c.2608C>T), located in coding exon 20 of the MYH7 gene, results from a C to T substitution at nucleotide position 2608. The arginine at codon 870 is replaced by cysteine, an amino acid with highly 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 detected in several unrelated probands reported to have hypertrophic cardiomyopathy (HCM) (Anan R et al. Hum Mutat, 2000 Jun;15:584; Woo A et al. Heart, 2003 Oct;89:1179-85; Otsuka H et al. Circ J, 2012 Nov;76:453-61; 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; Mak TSH et al. Sci Rep, 2018 Jul;8:10846; Hayashi T et al. J Hum Genet, 2018 Sep;63:989-996; Kim HY et al. J Clin Med, 2020 Jun;9). A different variant affecting this codon (p.R870H, c.2609G>A) has also been reported in association with HCM (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.79
MVP		0.97
MPC		2.4
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.54
gMVP		1.0

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: rs138049878; hg19: chr14-23894049; COSMIC: COSV62519739;