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rs727504240

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4_ModeratePM2PM1PP3PP1

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.2080C>T (p.Arg694Cys) has been identified in at least 15 individuals with HCM, including 3 who also carried other potentially disease-causing variants (PS4_Moderate; Andersen 1999 PMID:10563488; Havndrup 2003 PMID:12566107; Andersen 2004 PMID:15114369; Van Driest 2004 PMID:15358028; Van Driest 2004 PMID:15519027; Olivotto 2008 PMID:18533079; Ho 2009 PMID:20031602; Jensen 2013 PMID:23197161; Witjas-Paalberends 2013 PMID:23674513; Coppini 2014 PMID:25524337; Alfares 2015 PMID:25611685; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry pers. comm; GeneDx pers. comm; Invitae pers. comm; LMM pers. comm). This variant segregated with disease in 4 affected relatives with HCM from 2 families (PP1; Andersen 2004 PMID:15114369; GeneDx pers. comm.). This variant was identified in 0.001% (FAF 95% CI; 4/113682) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM2, PM1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA011642/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

16
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 4.72

Publications

12 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 Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • dilated cardiomyopathy 1S
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • hypertrophic cardiomyopathy 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • MYH7-related skeletal myopathy
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
  • myopathy, myosin storage, autosomal recessive
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • myopathy, myosin storage, autosomal dominant
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • congenital myopathy 7A, myosin storage, autosomal dominant
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Ebstein anomaly
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hyaline body myopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • left ventricular noncompaction
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • congenital heart disease
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
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

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
MYH7
NM_000257.4
MANE Select
c.2080C>Tp.Arg694Cys
missense
Exon 19 of 40NP_000248.2P12883
MYH7
NM_001407004.1
c.2080C>Tp.Arg694Cys
missense
Exon 18 of 39NP_001393933.1P12883

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
MYH7
ENST00000355349.4
TSL:1 MANE Select
c.2080C>Tp.Arg694Cys
missense
Exon 19 of 40ENSP00000347507.3P12883
MYH7
ENST00000858540.1
c.2080C>Tp.Arg694Cys
missense
Exon 19 of 40ENSP00000528599.1
MYH7
ENST00000965955.1
c.2080C>Tp.Arg694Cys
missense
Exon 19 of 40ENSP00000636014.1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
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
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
251358
AF XY:
0.0000221
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461872
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727232
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26136
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000899
AC:
10
AN:
1112000
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41450
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000187
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

ClinVar submissions
Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
5
-
-
Hypertrophic cardiomyopathy (5)
4
-
-
not provided (4)
1
-
-
Cardiomyopathy (1)
1
-
-
Cardiovascular phenotype (1)
1
-
-
Hypertrophic cardiomyopathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H
PhyloP100
4.7
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.8
D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0070
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.77
Gain of catalytic residue at L693 (P = 0)
MVP
0.97
MPC
2.4
ClinPred
0.98
D
GERP RS
5.0
Varity_R
0.74
gMVP
0.99
Mutation Taster
=7/93
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727504240; hg19: chr14-23895255; API
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