Genetic Variant NM_000257.4:c.4470G>C (chr14-23417202-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS4_SupportingPM2

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.4470G>C (p.Glu1490Asp) variant has been reported in 2 individuals with HCM (PS4_Supporting; GeneDx pers. comm., LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v.2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4_Supporting, PM2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA015001/MONDO:0005045/002

Frequency

Genomes: not found (cov: 33)

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.469

Publications

1 publications found

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:

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

MHRT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH7	NM_000257.4	MANE Select	c.4470G>C	p.Glu1490Asp	missense	Exon 32 of 40	NP_000248.2
MYH7	NM_001407004.1		c.4470G>C	p.Glu1490Asp	missense	Exon 31 of 39	NP_001393933.1
MHRT	NR_126491.1		n.652-10C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4470G>C	p.Glu1490Asp	missense	Exon 32 of 40	ENSP00000347507.3
MYH7	ENST00000858540.1		c.4470G>C	p.Glu1490Asp	missense	Exon 32 of 40	ENSP00000528599.1
MYH7	ENST00000965955.1		c.4470G>C	p.Glu1490Asp	missense	Exon 32 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

CardioboostCm

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

3.3

PhyloP100

0.47

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.059

Polyphen

1.0

Vest4

0.69

MutPred

0.53

Loss of methylation at K1485 (P = 0.2045)

MVP

0.96

MPC

1.5

ClinPred

0.95

GERP RS

4.3

Varity_R

0.58

gMVP

0.81

Mutation Taster

=33/67

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over