rs727505294

chr14-23415385-G-Achr14-23415385-G-Cchr14-23415385-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP2PP3_Moderate

The NM_000257.4(MYH7):c.5279C>T(p.Thr1760Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1760K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9

Conservation

PhyloP100: 9.49

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23415385-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1526128.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5279C>T	p.Thr1760Met	missense_variant	36/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5279C>T	p.Thr1760Met	missense_variant	35/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5279C>T	p.Thr1760Met	missense_variant	36/40	1	NM_000257.4	P1
	ENST00000557368.1 linkuse as main transcript	n.47G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251484

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1760 of the MYH7 protein (p.Thr1760Met). This variant is present in population databases (rs727505294, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18409188, 20513729). ClinVar contains an entry for this variant (Variation ID: 180024). 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%. This variant disrupts the p.Thr1760 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18409188, 20513729; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 06, 2014

The Thr1760Met variant in MYH7 has been reported in 2 Caucasian individuals with HCM and segregated with disease in 1 affected relative; however, 6 affected mem bers from the same family did not carry this variant (Fokstuen 2008, Calore 2011 ). It was absent from large population studies. Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Thr1760Met variant is uncertain due to conflicting evidence. -

Dilated cardiomyopathy 1S

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 20, 2023

This missense variant replaces threonine with methionine at codon 1760 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 18409188, 20513729, 32004434). In one family, some of these individuals also carried a variant in the MYL2 gene that segregated with disease (PMID: 32004434). This variant has been identified in 5/282882 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. -

Myosin storage myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

MYH7-related skeletal myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Myopathy, myosin storage, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2016

The T1760M variant in the MYH7 gene has been reported previously in association with HCM in two unrelated individuals and was absent in approximately 500 controls, however, segregation studies were not performed (Fokstuen et al., 2008; Melacini et al, 2010). The T1760M variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The T1760M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, T1760M is classified in ClinVar as a variant of uncertain clinical significance by another clinical laboratory (SCV000206548.3; Landrum et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2023

The p.T1760M variant (also known as c.5279C>T), located in coding exon 34 of the MYH7 gene, results from a C to T substitution at nucleotide position 5279. The threonine at codon 1760 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Fokstuen S et al. Hum Mutat, 2008 Jun;29:879-85; Melacini P et al. Int J Cardiol, 2008 Aug;128:364-73; De Bortoli M et al. Circ Genom Precis Med, 2020 Apr;13:e002824; Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

CardioboostCm

Uncertain

0.89

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.34

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

2.9

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.92

MutPred

0.39

Loss of phosphorylation at T1760 (P = 0.0163);

MVP

0.99

MPC

1.4

ClinPred

0.95

GERP RS

5.4

Varity_R

0.46

gMVP

0.90

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