14-23426809-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):c.2012G>A(p.Arg671His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R671C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MYH7
NM_000257.4 missense
NM_000257.4 missense
Scores
17
2
1
Clinical Significance
Conservation
PhyloP100: 7.69
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 strand (size 8) in uniprot entity MYH7_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr14-23426810-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 14-23426809-C-T is Pathogenic according to our data. Variant chr14-23426809-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 exome
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2
AN:
1461888
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32
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1
AN XY:
727244
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 01, 2024 | p.Arg671His (CGT>CAT): c.2012 G>A in exon 18 of the MYH7 gene (NM_000257.2). A variant of unknown significance has been identified in the MYH7 gene. The R671H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R671H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in the same residue (R671C) and in nearby residues (R663S, R663H, H668N) have been reported in association with cardiomyopathy, supporting the functional importance of this residue and this region of the protein. However, R671H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s). - |
| Uncertain significance, flagged submission | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Nov 09, 2016 | p.Arg671His (c.2012 G>A) in exon 18 of the MYH7 gene (NM_000257.2) Seen in a patient in our center with HCM and a family history of HCM. Tested at GeneDx. Given the lack of case data, position, and apparent rarity, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). I could find no cases of this variant reported in association with disease. The only submission in ClinVar is from the testing lab (as of Nov 9th, 2016). The variant is not present in the current SHaRe dataset (as of Nov 9th, 2016). The variant is in the head of myosin, which is enriched for pathogenic variation. However, when our team dissected which portions of the head are enriched for pathogenic variation this amino acid position did not come up as enriched in cases (Homburger et al 2016). There is no variation at codon 671 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. The average coverage at that site in gnomAD doe snot seem to be available, however coverage at a neighboring variant is good and the read data for that variant suggests that there is good coverage at this site as well. The variant is also not in ExAC and median coverage is 50x. - |
Hypertrophic cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 17, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 671 of the MYH7 protein (p.Arg671His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25132132; Invitae). ClinVar contains an entry for this variant (Variation ID: 181357). 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.Arg671 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 12820698, 25132132, 27532257; Invitae). 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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 18, 2024 | The p.R671H variant (also known as c.2012G>A), located in coding exon 16 of the MYH7 gene, results from a G to A substitution at nucleotide position 2012. The arginine at codon 671 is replaced by histidine, an amino acid with highly similar 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 alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Bagnall RD et al. Circ Genom Precis Med, 2022 Dec;15:e003686). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Hypertrophic cardiomyopathy 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Jan 03, 2022 | The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYH7 related disorder (ClinVar ID: VCV000181357, PMID:25132132, PS1_P). A different missense change at the same codon has been reported to be associated with MYH7 related disorder (ClinVar ID: VCV000164350, PMID:12707239, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, 3CNET: 0.982, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at R671 (P = 0.0042);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at