rs149193520

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4

The NM_000257.4(MYH7):c.5519T>C(p.Met1840Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000416 in 1,611,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. M1840L) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 4.45

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 0 ACMG points.

PP2

Missense variant where missense usually causes diseases, MYH7

BP4

Computational evidence support a benign effect (MetaRNN=0.38137627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.5519T>C	p.Met1840Thr	missense_variant	37/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.5519T>C	p.Met1840Thr	missense_variant	36/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5519T>C	p.Met1840Thr	missense_variant	37/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249958

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135302

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1459404

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726150

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

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:

0.0000294

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 25, 2023	This missense variant replaces methionine with threonine at codon 1840 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 reported for this variant. This variant has been reported in two individuals in one family affected with non-syndromic congenital heart defects (PMID: 25931334); these individuals also carried a pathogenic variant in the TBX5 gene. This variant has been identified in 9/281334 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This missense variant replaces methionine with threonine at codon 1840 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 reported for this variant. This variant has been reported in two individuals in one family affected with non-syndromic congenital heart defects (PMID: 25931334); these individuals also carried a pathogenic variant in the TBX5 gene. This variant has been identified in 9/281334 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 specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2018	Variant summary: MYH7 c.5519T>C (p.Met1840Thr) results in a non-conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 275678 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5519T>C, has been reported in the literature in two individuals in one family affected with congenital heart defects, co-occurring with the pathogenic variant TBX5 c.709C>T (p.Arg237Trp) (Jia_2015). This report provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 15, 2020

Has not been previously published in association with MYH7-related disorders to our knowledge; Reported in ClinVar (ClinVar Variant ID# 234383; Landrum 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: 23403236) -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1840 of the MYH7 protein (p.Met1840Thr). This variant is present in population databases (rs149193520, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 234383). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The p.M1840T variant (also known as c.5519T>C), located in coding exon 35 of the MYH7 gene, results from a T to C substitution at nucleotide position 5519. The methionine at codon 1840 is replaced by threonine, an amino acid with similar properties. This variant co-occurred with a variant in the TBX5 gene in affected individuals from a family with congenital heart defects (Jia Y et al. Am. J. Med. Genet. A, 2015 Aug;167A:1822-9). This variant has also been detected in an exome cohort; however, clinical details were limited (Sapp JC et al. Am. J. Hum. Genet., 2018 09;103:358-366). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

0.23

CardioboostCm

Benign

0.0087

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.63

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.38

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

0.85

MutationTaster

Benign

0.97

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.34

Sift

Uncertain

0.0090

Sift4G

Benign

0.11

Polyphen

0.070

Vest4

0.30

MVP

0.82

MPC

0.71

ClinPred

0.13

GERP RS

5.4

Varity_R

0.34

gMVP

0.71

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