rs730880786
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000257.4(MYH7):āc.3977A>Gā(p.Lys1326Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,605,636 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.000045 ( 0 hom. )
Consequence
MYH7
NM_000257.4 missense
NM_000257.4 missense
Scores
4
7
9
Clinical Significance
Conservation
PhyloP100: 7.80
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 Uncertain_significance. Variant got 3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, MYH7
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.873
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.3977A>G | p.Lys1326Arg | missense_variant | 30/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.3977A>G | p.Lys1326Arg | missense_variant | 29/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.3977A>G | p.Lys1326Arg | missense_variant | 30/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000122 AC: 3AN: 246668Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 133640
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GnomAD4 exome AF: 0.0000447 AC: 65AN: 1453462Hom.: 0 Cov.: 32 AF XY: 0.0000457 AC XY: 33AN XY: 721748
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces lysine with arginine at codon 1326 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with an inherited arrhythmia syndrome (PMID: 26743238). This variant has been identified in 3/246668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 02, 2023 | This missense variant replaces lysine with arginine at codon 1326 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with an inherited arrhythmia syndrome (PMID: 26743238). This variant has been identified in 3/246668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2013 | p.Lys1326Arg (AAG>AGG): c.3977 A>G in exon 30 of the MYH7 gene (NM_000257.2). The Lys1326Arg variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Lys1326Arg results in a conservative amino acid substitution of one positively charged amino acid with another at a position that is conserved across species. In silico analysis predicts Lys1326Arg is probably damaging to the protein structure/function. Mutations in nearby residues (Asn1327Lys, Ala1332Thr) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. However, data from control individuals were not available to assess whether Lys1326Arg may be a common benign variant in the general population. With the clinical and molecular information available at this time, we cannot definitively determine if Lys1326Arg is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 01, 2020 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2022 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1326 of the MYH7 protein (p.Lys1326Arg). This variant is present in population databases (rs730880786, gnomAD 0.002%). This missense change has been observed in individual(s) with an inherited arrhythmia syndrome (PMID: 26743238). ClinVar contains an entry for this variant (Variation ID: 181237). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2021 | The p.K1326R variant (also known as c.3977A>G), located in coding exon 28 of the MYH7 gene, results from an A to G substitution at nucleotide position 3977. The lysine at codon 1326 is replaced by arginine, an amino acid with highly similar properties. This variant has been detected in a cohort of patients with arrhythmias and cardiomyopathies; however, details were limited (Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
D
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Loss of ubiquitination at K1326 (P = 0.0041);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at