rs730880918

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BP4

The NM_000257.4(MYH7):​c.5786C>T​(p.Thr1929Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

1
2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.835
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a region_of_interest Disordered (size 28) in uniprot entity MYH7_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_000257.4
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.35080165).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH7NM_000257.4 linkc.5786C>T p.Thr1929Met missense_variant Exon 39 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.5786C>T p.Thr1929Met missense_variant Exon 38 of 39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.5786C>T p.Thr1929Met missense_variant Exon 39 of 40 1 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251214
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135836
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461736
Hom.:
0
Cov.:
32
AF XY:
0.0000248
AC XY:
18
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000279
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000223
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cardiomyopathy Uncertain:2
Mar 30, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 1929 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individual affected with hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 21839045, 28378410, 33495596). One of these individuals also carried a different pathogenic missense variant in the MYH7 (PMID: 28378410). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 28798025). This variant has been identified in 15/282610 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. -

Jul 29, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 1929 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 21839045, 28378410, 32894683, 33495596, 33495597, 38938358). One of these individuals also carried a different pathogenic variant in the same gene (PMID: 28378410) and another individual also carried a variant in the FHOD3 gene (PMID: 38938358). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 28798025, 33500567). This variant has been identified in 15/282610 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
Feb 07, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Michels et al., 2009; Kubo et al., 2011; Maron et al., 2012; van Velzen et al., 2016; Pajusalu et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25961035, 21799269, 15358028, 28798025, 28378410, 19666645, 21839045, 27247418, 34426522, 32894683, 27476098, 34542152) -

Jan 19, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1
Oct 15, 2015
Blueprint Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:1
Nov 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1929 of the MYH7 protein (p.Thr1929Met). This variant is present in population databases (rs730880918, gnomAD 0.009%). This missense change has been observed in individual(s) with left ventricular noncompaction and hypertrophic cardiomyopathy (PMID: 15358028, 19666645, 21799269, 28798025). ClinVar contains an entry for this variant (Variation ID: 181397). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH7 protein function with a negative predictive value of 95%. 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
Oct 15, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.T1929M variant (also known as c.5786C>T), located in coding exon 37 of the MYH7 gene, results from a C to T substitution at nucleotide position 5786. The threonine at codon 1929 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Kubo T et al. Circ. J., 2011 Jul;75:2654-9). This alteration was reported in a proband and three asymptomatic family members (Michels M et al. Eur. Heart J., 2009 Nov;30:2593-8) and has also been reported in conjunction with a second missense alteration in MYH7 (Maron BJ et al. Heart Rhythm, 2012 Jan;9:57-63). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
CardioboostCm
Benign
0.0080
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.33
T
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.81
T
M_CAP
Pathogenic
0.75
D
MetaRNN
Benign
0.35
T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
1.9
L
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.2
N
REVEL
Uncertain
0.52
Sift
Benign
0.078
T
Sift4G
Benign
0.089
T
Polyphen
0.35
B
Vest4
0.20
MVP
0.79
MPC
0.62
ClinPred
0.13
T
GERP RS
4.7
Varity_R
0.054
gMVP
0.24

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: rs730880918; hg19: chr14-23882972; API