rs767300277

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000257.4(MYH7):c.5779A>T(p.Ile1927Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I1927I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 1.04

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]

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a region_of_interest Disordered (size 28) in uniprot entity MYH7_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_000257.4

PP2

Missense variant where missense usually causes diseases, MYH7

BP4

Computational evidence support a benign effect (MetaRNN=0.23254982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5779A>T	p.Ile1927Phe	missense_variant	39/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5779A>T	p.Ile1927Phe	missense_variant	38/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5779A>T	p.Ile1927Phe	missense_variant	39/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251320

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces isoleucine with phenylalanine at codon 1927 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 performed for this variant. This variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18409188, 20624503, 20800588, 21239446, 23140321, 27574918, 28771489, 30696458, 32268277, 33495597). One of these individuals also carried another pathogenic variant in the MYBPC3 gene (PMID: 20624503). This variant has been reported in three related individuals (PMID: 26497160). Two of them were affected with hypertrophic cardiomyopathy, and also carried a pathogenic variant in the MYL2 gene that could explain the observed phenotype. The other carrier in the family was not diagnosed with cardiovascular disease. This variant has been reported in an individual affected with limb-girdle muscular dystrophy with no cardiac involvement (PMID: 25214167, 27387980). This variant has also been identified in 13/282718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been reported in multiple affected individuals, it has also been reported in individuals carrying different pathogenic variants that could explain the observed disease, as well as in individuals with no cardiac involvement. 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	Mar 08, 2023	This missense variant replaces isoleucine with phenylalanine at codon 1927 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 performed for this variant. This variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18409188, 20624503, 20800588, 21239446, 23140321, 27574918, 28771489, 30696458, 32268277, 33495597). One of these individuals also carried another pathogenic variant in the MYBPC3 gene (PMID: 20624503). This variant has been reported in three related individuals (PMID: 26497160). Two of them were affected with hypertrophic cardiomyopathy, and also carried a pathogenic variant in the MYL2 gene that could explain the observed phenotype. The other carrier in the family was not diagnosed with cardiovascular disease. This variant has been reported in an individual affected with limb-girdle muscular dystrophy with no cardiac involvement (PMID: 25214167, 27387980). This variant has also been identified in 13/282718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been reported in multiple affected individuals, it has also been reported in individuals carrying different pathogenic variants that could explain the observed disease, as well as in individuals with no cardiac involvement. 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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 06, 2023	- -

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2022	Observed in multiple individuals with HCM in the published literature and at GeneDx, however, at least one family harbored a co-occurring pathogenic variant (Fokstuen et al, 2008; Millat et al, 2010; Claes et al., 2016; Gomez et al., 2017); Reported in an individual with childhood onset axial and distal limb weakness and no cardiac involvement or known family history (Fiorillo et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28356264, 21239446, 20624503, 27387980, 32268277, 26497160, 25214167, 18409188) -

Wolff-Parkinson-White pattern

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1927 of the MYH7 protein (p.Ile1927Phe). This variant is present in population databases (rs767300277, gnomAD 0.009%). This missense change has been observed in individual(s) with myopathy and HCM (PMID: 18409188, 20624503, 27387980, 28356264). ClinVar contains an entry for this variant (Variation ID: 487639). 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 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. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 13, 2017

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The p.I1927F variant (also known as c.5779A>T), located in coding exon 37 of the MYH7 gene, results from an A to T substitution at nucleotide position 5779. The isoleucine at codon 1927 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in several hypertrophic cardiomyopathy cohorts, and sometimes in individuals who had variants in other cardiac-related genes (Fokstuen S et al. Hum. Mutat. 2008;29:879-85; Millat G et al. Eur J Med Genet;53:261-7; Teirlinck CH et al. BMC Med. Genet. 2012;13:105; Lopes LR et al. Heart. 2015;101:294-301; Claes GR et al. Eur. Heart J. 2016;37:1815-22; Jaafar N et al. Genet Test Mol Biomarkers, 2016 Nov;20:674-679; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:[ePub ahead of print]). This variant was also detected in an individual with axial and distal upper and lower limb weakness but no cardiac involvement (Fiorillo C et al. Orphanet J Rare Dis. 2016;11:91). This amino acid position is not well 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

0.084

CardioboostCm

Uncertain

0.24

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Uncertain

-0.070

Cadd

Benign

Dann

Benign

0.81

DEOGEN2

Benign

0.31

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.94

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.86

REVEL

Uncertain

0.47

Sift

Benign

0.68

Sift4G

Benign

0.89

Polyphen

0.43

Vest4

0.32

MutPred

0.21

Gain of catalytic residue at I1927 (P = 0.0632);

MVP

0.88

MPC

0.92

ClinPred

0.080

GERP RS

5.6

Varity_R

0.11

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over