rs727504311

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The ENST00000355349.4(MYH7):​c.2543A>G​(p.Glu848Gly) 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. 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. E848D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH7
ENST00000355349.4 missense

Scores

14
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.61
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 17 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, 9 uncertain in ENST00000355349.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-23424904-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181374.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.927
PP5
Variant 14-23424905-T-C is Pathogenic according to our data. Variant chr14-23424905-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23424905-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH7NM_000257.4 linkuse as main transcriptc.2543A>G p.Glu848Gly missense_variant 22/40 ENST00000355349.4 NP_000248.2
MYH7NM_001407004.1 linkuse as main transcriptc.2543A>G p.Glu848Gly missense_variant 21/39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkuse as main transcriptc.2543A>G p.Glu848Gly missense_variant 22/401 NM_000257.4 ENSP00000347507 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 10, 2018The p.Glu848Gly variant in MYH7 has been identified in at least 6 individuals wi th HCM and segregated with disease in one affected family member (Alfares 2015, GeneDx pers. comm., LMM data). This variant was absent from large population stu dies. In vitro functional studies provide some evidence that the p.Glu848Gly va riant may impact protein function (Pioner 2016); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Glu848Gly variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. Of note, this variant lies in the head region of the protein. Missense vari ants in this region have been reported and statistically indicated to be more li kely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu848Gly variant i s likely pathogenic. ACMG/AMP criteria applied: PM1, PM2, P23_Moderate, PS4_Mode rate, PP3. -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 848 of the MYH7 protein (p.Glu848Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27161364, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 177758). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 30623132). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJun 22, 2020Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 177758; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Functional studies using stem cells suggest that this variant changes contractile properties leading to cardiomyopathy (Pioner et al., 2016; Yang 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: 27532257, 27161364, 25611685, 28606303, 30623132) -
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 05, 2019Variant summary: MYH7 c.2543A>G (p.Glu848Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246248 control chromosomes (gnomAD). It is reported in the Atlas of Cardiac Genetic Variation database to occur in the region enriched for HCM mutations (residues 181-937) and is scored with a high etiological fraction (0.97) (in general, missense variants in MYH7 have an overall etiological fraction of 0.92). c.2543A>G has been reported in the literature in an individual affected with Hypertrophic Cardiomyopathy (Alfares_2015) and was shown to co-segregate with disease in a pedigree affected with familial cardiomyopathy (FCM) with adult-onset systolic dysfunction (Yang_2018). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact on protein function report this variant to result in contractile dysfunction of myofibrils (Pioner_2016) by disruption of the myosin S2 and cMyBP-C C1C2 protein-protein interaction (Yang_2018; Pioner_2016) on measures of maximal isometric tension generation (Pioner_2016) and lack of growth in yeast-two hybrid assay (Yang_2018). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
CardioboostCm
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.91
D
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.93
D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
4.5
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-5.6
D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.40
Gain of MoRF binding (P = 0.0245);
MVP
0.96
MPC
2.3
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.59
gMVP
0.99

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: rs727504311; hg19: chr14-23894114; API