14-23425345-C-T

Position:

chr14-23425345-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. BP2PM1BS1

This summary comes from the ClinGen Evidence Repository: The c.2360G>A (p.Arg787His) variant in MYH7 has been identified in 0.10% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID:29300386). Additionally, while 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), this pathogenic evidence code (PM1) was not considered to be in conflict with a likely benign conclusion. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012239/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:9B:14

Conservation

PhyloP100: 0.766

Variant links:

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]

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

BP2

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2360G>A	p.Arg787His	missense_variant	21/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.2360G>A	p.Arg787His	missense_variant	20/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2360G>A	p.Arg787His	missense_variant	21/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251472

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000179

AC:

262

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

169

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00227

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000471

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:9Benign:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2019	Variant summary: MYH7 c.2360G>A (p.Arg787His) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251472 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.039 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH7 causing Cardiomyopathy phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2360G>A has been reported in the literature in multiple individuals affected with Cardiomyopathy. However, the variant has also been observed in multiple families that showed lack of cosegregation with disease including unaffected individuals with the variant and affected individuals without the variant (Purushotham_2010, Laredo_2006). In addition, the variant has been observed to co-occur with other pathogenic variants, MYBPC3 c.3641G>A, p.W1214X; MYH7, I736T), providing supporting evidence for a benign role. A functional study, Sequeira_2013, indicates the variant to have higher Ca 2+ sensitivity and low phosphorylation of protein kinase A targets compared to donors, along with length-dependent activation being significantly smaller. Ten ClinVar submissions (evaluation after 2014) cite the variant five times as likely benign, while five other submissions including the expert panel, ClinGen, cite the variant as uncertain signfiicance. In addition, another variant affecting the same codon, R787C, has been reported in affected individuals suggesting the location could be important for protein function. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2013	The Arg787His variant has been reported in 7 probands (6 with HCM and 1 with DCM ), has been detected by our laboratory in 4 additional individuals with HCM. The majority of these individuals were of Indian or Arabic descent (Richard 2003, Y u 2005, Laredo 2006, Boda 2009, Rai 2009, Purushotham 2010; LMM unpublished data ). Three of 11 probands (2: LMM, 1: Laredo 2006) carried a second variant suffi cient to explain their disease. The variant was present in 1/4406 African Americ an chromosomes from a broad population screened by the NHLBI Exome Sequencing pr oject (http://evs.gs.washington.edu/EVS) but absent from 600 were race-matched c hromosomes (Purushotham 2010) and 600 additional chromosomes across several stud ies (Richard 2003, Yu 2005, Laredo 2006, Boda 2009, Rai 2009). Another variant a t the same position (Arg787Cys) has been reported in individuals with HCM (Morit a 2008, Garcia-Castro 2009); however, the affected amino acid (arginine) is only moderately conserved in evolution, suggesting that a change may be tolerated or be milder. A milder effect was also suspected by Purushotham 2010 who detected the variant in 2 affected individuals but also 8 asymptomatic relatives. Of not e, one of these families had a history of sudden death including the son of an i ndividual who tested negative for the Arg787His variant. While a phenocopy cann ot be ruled out this possible non-segregation raises concern regarding the patho genicity of the Arg787His variant. In summary, the data for this variant is some what conflicting and additional studies are needed to clarify its role in diseas e. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 09, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 29, 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 p.Arg787His We consider this a variant of uncertain significance, likely disease causing, based on the co-occurrence of another pathogenic variant in several of the cases with multi-gene sequencing and the possible failure to segregate in one family. The variant has been seen in at least 9 unrelated cases of cardiomyopathy (not including the patient). Three patients had another variant sufficient to explain their disease. Five of the other cases had insufficient sequencing to determine if another variant was present. There is weak segregation data in two families, though in one of them there is potential for failure to segregate with insufficient information available. Richard P et al., 2003 first described this variant in a European individual with HCM. They sequenced 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC and TNNC1) in 197 unrelated index cases with HCM. Patients were recruited from France and most of them were of European origin. No details regarding this patient's phenotype was given. Yu et al (2005) observed the variant in one of 150 patients with HCM from their Australian cohort. They reported only on analysis of MYH7. Laredo et al (2006) reported this variant in a 43 year old Spanish female, who also harbored p.Ile736Thr variant in the MYH7 gene (which we classify as likely disease causing). They sequenced MYH7 in 128 patients with HCM to compare the phenotypes of those with and without mutations in MYH7. The patient who harbored this variant in addition to the p.Ile736Thr variant in MYH7 was a female diagnosed at age 43 with a maximum thickness of 30mm and asymmetric hypertrophic morphology. The patient's mother was diagnosed with HCM at age 43 and had undergone a myectomy and died from heart failure at age 69. It appears that the father tested negative for both variants. The patient's sons both inherited only the p.Ile736Thr variant, revealing that these variants were in trans. Her eldest son had some hypertrophy with maximal thickness of 11mm at age 21. Her youngest son had maximal thickness of 13mm with asymmetric hypertrophy at age 16. None of the studied family members had just p.Arg787His. Boda et al (2009) observed the variant in one of 100 idiopathic DCM cases in their Indian cohort. They analyzed MYH7, TNNI3, ACTC. Rai et al (2009) observed the variant in one of 69 patients with HCM in their Indian cohort. They only analyzed MYH7. Purushotham et al. (2010) reported this variant in two unrelated Indian patients with HCM. The authors sequenced exons 3-23 of the MYH7 gene and all exons of the MYBPC3 gene. The authors did not sequence other genes in the patients identified to carry the p.Arg787His variant. In each family there were two affected first degree relatives who carry the variant. Of note, in one of these families there was an "uninvestigated sudden death" in the child of someone who tested negative for the variant, suggesting a possible failure to segregate. This variant is located in exon 21 of the MYH7 gene. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The arginine at codon 787 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg787Cys) and nearby codons (Ser782Asn; Arg783His, Arg793Gln). Purushotham and colleagues presented some functional data which suggested that this substitution is not tolerated. Sequence and structure analysis of the MYH7 mutation revealed that the mutant protein might be compromised in its ability to bind essential light chain efficiently. The authors suggested that the MYH7 p.Arg787His variant may resu -

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	This variant is associated with the following publications: (PMID: 17125710, 29343710, 20086309, 12707239, 31006259, 20664766, 20433692, 21959974, 22957257, 23299917, 25228707, 25637381, 27247418, 28518168, 30731207, 29300372, 30847666, 31638223) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hypertrophic cardiomyopathy 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 10, 2017	The MYH7 Arg787His variant occurs in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.02%. In silico tools (SIFT, PolyPhen-HCM, MutationTaster) are in support of a benign role. The MHY7 Arg787His variant was identified in a HCM proband with no family history of disease. The proband also harbours 2 additional MYBPC3 variants (p.Ala693Val & p.Arg817Gly) that are likely contributing to the disease phenotype. A second individual with non-diagnostic hypertrophy was also identified with this variant. Based on the high frequency in the general population and in silico tool predicting a benign effect, we classify MYH7 Arg787His as "likely benign". -

Primary familial hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 27, 2017	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 19, 2020	- -

Hypertrophic cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Apr 27, 2021	The c.2360G>A (p.Arg787His) variant in MYH7 has been identified in 0.10% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while 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), this pathogenic evidence code (PM1) was not considered to be in conflict with a likely benign conclusion. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, PM1. -

Dilated cardiomyopathy 1S

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MYH7-related skeletal myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Myosin storage myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Left ventricular noncompaction cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostCm

Uncertain

0.51

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Benign

-0.0050

Eigen_PC

Benign

-0.017

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.57

Sift

Benign

0.23

Sift4G

Benign

0.54

Polyphen

0.81

Vest4

0.82

MVP

0.96

MPC

1.2

ClinPred

0.051

GERP RS

4.6

Varity_R

0.27

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over