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rs121913627

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1PM1PM2PM5PP2PP3

The NM_000257.4(MYH7):c.1816G>T(p.Val606Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V606M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH7
NM_000257.4 missense

Scores

8
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54
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.

PS1
Transcript NM_000257.4 (MYH7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr14-23427657-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, MYH7
PP3
MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYH7NM_000257.4 linkuse as main transcriptc.1816G>T p.Val606Leu missense_variant 16/40 ENST00000355349.4
MYH7NM_001407004.1 linkuse as main transcriptc.1816G>T p.Val606Leu missense_variant 15/39

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH7ENST00000355349.4 linkuse as main transcriptc.1816G>T p.Val606Leu missense_variant 16/401 NM_000257.4 P1

Frequencies

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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 17, 2017A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant has not been reported in the literature in individuals with MYH7-related disease. It has, however, been reported in an unaffected individual (PMID: 24704860). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 606 of the MYH7 protein (p.Val606Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. A different missense substitution at this codon (p.Val606Met) has been determined to be pathogenic (PMID: 27532257, 1552912, 9172070, 18020371). This suggests that the valine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
CardioboostCm
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.87
D
Eigen
Benign
-0.062
Eigen_PC
Benign
0.025
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.76
D
MetaSVM
Uncertain
0.056
D
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-2.6
D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.020
D
Sift4G
Uncertain
0.0090
D
Polyphen
0.0070
B
Vest4
0.54
MutPred
0.73
Gain of catalytic residue at L608 (P = 0.0142);
MVP
0.90
MPC
1.5
ClinPred
0.93
D
GERP RS
5.1
Varity_R
0.66
gMVP
0.68

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: rs121913627; hg19: chr14-23896866; API