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rs727503278

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.427C>T(p.Arg143Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,036 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. R143Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

14
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 0.193
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000257.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-23432713-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43006.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, 0.98
PP5
Variant 14-23432714-G-A is Pathogenic according to our data. Variant chr14-23432714-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23432714-G-A is described in Lovd as [Pathogenic]. Variant chr14-23432714-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYH7NM_000257.4 linkuse as main transcriptc.427C>T p.Arg143Trp missense_variant 5/40 ENST00000355349.4
MYH7NM_001407004.1 linkuse as main transcriptc.427C>T p.Arg143Trp missense_variant 4/39

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH7ENST00000355349.4 linkuse as main transcriptc.427C>T p.Arg143Trp missense_variant 5/401 NM_000257.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251480
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461886
Hom.:
0
Cov.:
33
AF XY:
0.0000124
AC XY:
9
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxMay 31, 2023Observed in individuals with cardiomyopathy and/or sudden cardiac death and in unaffected relatives from three families, including one family in which the variant was identified in trans with another MYH7 variant (Hershkovitz et al., 2019); Reported in a 32 year-old male with a family history of sudden cardiac death, who also harbored a splice site variant in the TPM1 gene (Maron et al., 2012); Located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018); 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: 17947214, 19864899, 21839045, 25086479, 26914223, 27532257, 28615295, 28193612, 12974739, 23711808, 8981935, 3203908, 7909436, 17372140, 25666907, 8614836, 7883988, 20733148, 15322983, 12820698, 24093860, 15563892, 15358028, 18383048, 28771489, 22455086, 30588760, 31447099, 33309763, 32894683, 32344918, 33673806, 34542152, 34598319, 24510615, 35653365) -
Likely pathogenic, no assertion criteria providedprovider interpretationStanford Center for Inherited Cardiovascular Disease, Stanford UniversityOct 16, 2017p.Arg143Trp (c.427C>T) in the MYH7 gene (NM_000257.3) chr14-23901923-G-A rs727503278 Seen in one patient with HCM in our center. Given the case data and an additional pathogenic variant at the same amino acid position, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Because of its frequency in gnomAD, it has been classified as likely pathogenic and not pathogenic. It should also be re-reviewed periodically given its frequency in gnomAD. The variant has been seen in at least 10 unrelated cases of HCM (not including this patient's family), 5 patients referred for HCM genetic testing, 1 patient with DCM (and an MYH7 loss of function variant in trans). The possibility of overlap of patients is minimal since most of the case reports are published from varying institutions, unless otherwise noted below. There is strong case data and modrate segregation data. Erdmann et al (2003) saw this variant in 1 patient with HCM. Patients recruited were either Turkish, Greek, Italian, or German. Liu et al (2013) reports one patient with this variant, but the c.DNA position is listed as c.533C>T. Kapplinger et al (2014) saw this variant in 6 cases of HCM, (either diagnosed with HCM at Mayo or referred for HCM genetic testing). Chiou et al (2014) reports the variant in 1 Taiwanese patient with HCM. Nomenclature for cDNA is c.533C>T as well. Walsh (2016) reports this variant in 2 patients with clinical diagnosis of HCM. Mademont-Soler (2017) reports this variant in 1 index pt with HCM. Authors note that three other affected family members tested positive, but do not provide degree of relation or other clinical details. Ingles et al (2017) considered this variant pathogenic and have seen this variant in an HCM patient at their center. Maron BJ, et al. (2012) reports this variant in a 32yo male with HCM and family history of SCD who also harbored a splice variant in TPM1. Murphy et al. (2016) identified in 1 patient with HCM recruited from Mayo. This might not be a unique case as patients in this study had genetic testing at clinical labs including Transgenomic (which would be redundant with Kapplinger et al) and LMM. LMM: - a patient with DCM who carried an MYH7 loss of function variant in trans (there is an emerging hypothesis that MYH7 variants may contribute to cardiomyopathy risk in a recessive fashion). -a patient with HCM In Homburger et al 2016, the residue is enriched in HCM cases vs. ExAC. Another variant at the same residue R143Q has been reported as pathogenic/likely pathogenic by 7 laboratories in ClinVar. This R143Q variant has not been seen at our center, nor did I perform a complete review based on the data in ClinVar. It is only present in 1 European individual in gnomAD. The R143W variant has been seen in 7 in 123,126 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 2 of 8,624 East Asian individuals (MAF = 0.01160%), 4 of 55,850 European (NF) individuals (MAF = 0.003581%), and 1 of 15,391 South Asian individuals (MAF = 0.003249%). I checked the filtering allele frequency for this variant in ExAC and it passes the threshold for HCM. -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsNov 14, 2018- -
Hypertrophic cardiomyopathy Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 05, 2020proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 24, 2024This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the MYH7 protein (p.Arg143Trp). This variant is present in population databases (rs727503278, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 23711808, 25086479, 27532257, 28408708, 28615295, 28771489, 30588760). ClinVar contains an entry for this variant (Variation ID: 164401). 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.Arg143 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 15563892, 21252143, 22765922, 24093860). 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. -
Likely pathogenic, criteria provided, single submitterresearchAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteFeb 01, 2019This MYH7 Arg143Trp variant has previously been reported in HCM cohorts (Erdmann J et al., 2003; Van Driest SL et al., 2004; Maron BJ et al., 2011; Liu W et al., 2013; Kapplinger JD et al., 2014; Chiou KR et al., 2014; Mademont-Soler I et al., 2017; Walsh R et al., 2017), and has been been proven to segregate in one family (Mademont-Soler I et al., 2017). We have also identified this variant in one isolated HCM case (Ingles J et al., 2017). This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000028. Interestingly, a different rare variant at this position (Arg143Gln) has been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster and PolyPhen-2 predict this variant to be "deleterious". In summary, based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant this variant has been reported in more than 10 unrelated probands (PS4), is rare in the general population (PM2), segregates to affected individuals in one family (PP1) and in silico tools predict the variant is deleterious (PP3), therefore we classify this variant as 'likely pathogenic'. -
Cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 12, 2022This missense variant replaces arginine with tryptophan at codon 143 of the myosin head/motor (S1) domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 25086479, 26914223, 27532257, 28408708, 28193612, 30588760, 32344918, 33495596, 33495597, 34598319; ClinVar SCV000199274.4), as well as in six individuals affected with or suspected of having hypertrophic cardiomyopathy (PMID: 24510615). Four family members of these probands have been reported to be unaffected carriers (PMID: 30588760). This variant has also been identified in a case of fetal left ventricular noncompaction (PMID: 33309763). This variant has been identified in 7/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg143Gln (Clinvar variation ID 43006), is known to cause familial hypertrophic cardiomyopathy, suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioApr 29, 2021- -
Hypertrophic cardiomyopathy 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Region OstergotlandMay 27, 2019PS4, PM5, PP3 -
Pathogenic, criteria provided, single submitterclinical testingKardioGenetik, Herz- und Diabeteszentrum NRWFeb 15, 2024- -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 12, 2017- -
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute-- -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 13, 2023The p.R143W variant (also known as c.427C>T), located in coding exon 3 of the MYH7 gene, results from a C to T substitution at nucleotide position 427. The arginine at codon 143 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported multiple times in hypertrophic cardiomyopathy (HCM) cohorts (e.g., Erdmann J et al. Clin. Genet. 2003;64:339-49; Chiou KR et al. J Cardiol. 2015;65:250-6; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Walsh R et al. Genet. Med. 2017;19:192-203). Two other alterations in the same codon, p.R143Q and p.R143G, have also been associated with HCM (Mohiddin SA et al. Genet. Test, 2003;7:21-7; Song L et al. Clin. Chim. Acta. 2005;351:209-16). This amino acid position is highly 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
Pathogenic
0.95
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.29
Cadd
Uncertain
24
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
D
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.5
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-5.4
D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0060
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.79
Gain of catalytic residue at Y142 (P = 2e-04);
MVP
0.98
MPC
2.2
ClinPred
0.92
D
GERP RS
2.6
Varity_R
0.69
gMVP
0.95

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

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

Other links and lift over

dbSNP: rs727503278; hg19: chr14-23901923; COSMIC: COSV62520487; API