14-23425316-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_000257.4(MYH7):​c.2389G>C​(p.Ala797Pro) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A797T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH7
NM_000257.4 missense

Scores

7
7
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: -0.114
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 12 ACMG points.

PM1
In a domain IQ (size 29) in uniprot entity MYH7_HUMAN there are 19 pathogenic changes around while only 1 benign (95%) 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 chr14-23425316-C-T 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, 0.958
PP5
Variant 14-23425316-C-G is Pathogenic according to our data. Variant chr14-23425316-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1476852.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr14-23425316-C-G is described in Lovd as [Pathogenic]. Variant chr14-23425316-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH7NM_000257.4 linkc.2389G>C p.Ala797Pro missense_variant Exon 21 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.2389G>C p.Ala797Pro missense_variant Exon 20 of 39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.2389G>C p.Ala797Pro missense_variant Exon 21 of 40 1 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

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

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1
Jul 13, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). 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. This variant disrupts the p.Ala797 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10521296, 17125710). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 17125710; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 797 of the MYH7 protein (p.Ala797Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. -

Cardiovascular phenotype Uncertain:1
Nov 12, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.A797P variant (also known as c.2389G>C), located in coding exon 19 of the MYH7 gene, results from a G to C substitution at nucleotide position 2389. The alanine at codon 797 is replaced by proline, 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 variant was identified in one or more individuals with features consistent with hypertrophic cardiomyopathy and segregated with disease in at least one family (Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18; Walsh R et al. Genet Med, 2017 Feb;19:192-203; external communication; Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
CardioboostCm
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.27
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.51
FATHMM_MKL
Benign
0.060
N
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.8
M
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-1.3
N
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0030
D
Sift4G
Benign
0.099
T
Polyphen
0.32
B
Vest4
0.84
MutPred
0.81
Gain of catalytic residue at V795 (P = 0);
MVP
0.90
MPC
2.1
ClinPred
0.60
D
GERP RS
0.75
Varity_R
0.65
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs3218716; hg19: chr14-23894525; API