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rs121913624

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.1208G>T(p.Arg403Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R403Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH7
NM_000257.4 missense

Scores

17
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.77
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000257.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-23429278-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14087.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, 0.97
PP5
Variant 14-23429278-C-A is Pathogenic according to our data. Variant chr14-23429278-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 14101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23429278-C-A is described in Lovd as [Pathogenic]. Variant chr14-23429278-C-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.1208G>T p.Arg403Leu missense_variant 13/40 ENST00000355349.4
MYH7NM_001407004.1 linkuse as main transcriptc.1208G>T p.Arg403Leu missense_variant 12/39

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH7ENST00000355349.4 linkuse as main transcriptc.1208G>T p.Arg403Leu missense_variant 13/401 NM_000257.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityJun 16, 2015Note 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. p.Arg403Leu (c.1208G>T) in MYH7 Based on the data reviewed below we consider this variant likely disease-associated. The variant has been seen in at least 3 unrelated cases of HCM with strong segregation data. The variant was first reported by Dausse et al (1993) in a large kindred in which linkage studies including 11 affected relatives pointed towards MYH7. Sequencing of MYH7 identified p.Arg403Leu and its presence was confirmed in 6 affected individuals. A subsequent publication that included some of the same authors reported an additional family that appears to be distinct from the initial report (Al-Mahdawi et al 1994). Three affected individuals and one obligate carrier carried p.Arg403Leu. Richard et al (2003) reported the variant in one individual with HCM. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 403 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg403Gln and p.Arg403Trp, both very likely disease cuausing) and nearby codons (p.Arg404Leu, p.Arg404Met, p.Arg406Met, p.Arg407Val). Moolman et al (1993) noted that there is a CpG doublet at codon 403 which may likely makes it susceptible to mutation. In total the variant has not been seen in 5150 published controls and publicly available population datsets. There is no variation at codon 403 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/14/2012). There is also no variation at this codon listed in 1000 genomes (as of 1/14/2012). p.Arg403Gln is not listed in dbSNP (as of 1/14/2012). The variant was not observed in the following published control samples: 50 (Al-Mahdawi et al 1994), 100 (Richard et al 2003). -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 28, 2020Not observed in large population cohorts (Lek et al., 2016); 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: 30847666, 31006259, 27532257, 15386449, 12707239, 18227814, 24566549, 7731997, 7848420, 8254035) -
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeSep 11, 2020This sequence change replaces arginine with leucine at codon 403 of the MYH7 protein (p.Arg403Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8254035, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14101). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant disrupts the p.Arg403 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10725281, 23751935, 18029407, 10882745). 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. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 23, 2020The p.R403L pathogenic mutation (also known as c.1208G>T), located in coding exon 11 of the MYH7 gene, results from a G to T substitution at nucleotide position 1208. The arginine at codon 403 is replaced by leucine, an amino acid with dissimilar properties, and is located in the head domain. This variant has been reported in several unrelated individuals with hypertrophic cardiomyopathy (HCM), and has been reported to segregate with disease in families (Dausse E et al. J. Clin. Invest., 1993 Dec;92:2807-13; al-Mahdawi S et al. Br Heart J, 1994 Aug;72:105-11; Santos S et al. BMC Med. Genet. 2012 Mar;13:17; Walsh R et al. Genet. Med., 2017 02;19:192-203; Cui H et al. Orphanet J Rare Dis. 2019 11;14(1):252; Norrish G et al. Circulation, 2019 07;140:184-192). In addition, other pathogenic variants affecting this codon (p.R403Q, c.1208G>A and p.R403W, c.1207C>T) have also been reported in association with HCM (Dausse E et al. J. Clin. Invest., 1993 Dec;92:2807-13; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hypertrophic cardiomyopathy 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 1993- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
Cadd
Pathogenic
32
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D
Eigen
Pathogenic
0.77
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Pathogenic
2.9
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.1
D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.78
Gain of catalytic residue at R403 (P = 5e-04);
MVP
0.96
MPC
2.3
ClinPred
0.99
D
GERP RS
4.0
Varity_R
0.91
gMVP
0.97

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: rs121913624; hg19: chr14-23898487; API