14-23428631-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):​c.1447G>A​(p.Glu483Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

16
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 7.68
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PP2
Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 14-23428631-C-T is Pathogenic according to our data. Variant chr14-23428631-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23428631-C-T is described in Lovd as [Likely_pathogenic]. Variant chr14-23428631-C-T is described in Lovd as [Pathogenic]. Variant chr14-23428631-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH7NM_000257.4 linkc.1447G>A p.Glu483Lys missense_variant Exon 15 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.1447G>A p.Glu483Lys missense_variant Exon 14 of 39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.1447G>A p.Glu483Lys missense_variant Exon 15 of 40 1 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
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:
0.00000398
AC:
1
AN:
251460
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135916
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461860
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727232
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:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74330
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 1 Pathogenic:4
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 1999- -
Likely pathogenic, criteria provided, single submitterclinical testingClinical Genomics Laboratory, Washington University in St. LouisSep 23, 2024The MYH7 c.1447G>A (p.Glu483Lys) variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy and is reported to segregate with disease in six individuals in one family (Berge KE and Leren TP, PMID: 24111713; Richard P et al., PMID: 10424815; Walsh R et al., PMID: 27532257). Two of those individuals also harbored a pathogenic variant in MYBPC3 and displayed more severe hypertrophy than those with the MYH7 c.1447G>A variant alone (Richard P et al., PMID: 10424815). This variant is only observed on 2/282,856 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant resides within the myosin motor domain of MYH7 that is defined as a critical functional domain and is significantly overrepresented in individuals with hypertrophic cardiomyopathy (Walsh R et al., PMID: 27532257). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MYH7 function. This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by nine submitters and a variant of uncertain significance by one submitter. Based on available information, the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, this variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 06, 2021Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the myosin motor domain (NCBI, UniProt, PMID 29300372). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in at least ten individuals with HCM, and has sometimes been observed in a compound heterozygous state or in addition to another heterozygous variant, resulting in a more severe phenotype (Atlas of Cardiac Genetic Variation, ClinVar, HGMD, LOVD, PMIDs: 10424815, 24111713, 27532257 & 28378410). (SP) 0902 - This variant has moderate evidence for segregation with disease. The variant was shown to segregate with HCM over three generations in one family, with four affected heterozygotes, and an additional two heterozygotes with a more severe phenotype who also carried a pathogenic variant in the MYBPC3 gene (PMID: 10424815). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitterclinical testingNational Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of HealthAug 06, 2021- -
Hypertrophic cardiomyopathy Pathogenic:3Uncertain:1
Uncertain significance, flagged submissionresearchGenetics and Genomics Program, Sidra Medicine-- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 24, 2024This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 483 of the MYH7 protein (p.Glu483Lys). This variant is present in population databases (rs121913651, gnomAD 0.002%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10424815, 24111713, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 14, 2019The p.Glu483Lys variant in MYH7 has been reported in 5 individuals with HCM (Richard 1999, Berge 2014, Walsh 2017). One of these individuals also carried a nonsense variant in MYBPC3. Her affected son carried both variants and 4 additional affected family members carried only the p.Glu483Lys variant in MYH7. The proband and her son were reported to be more severely affected than family members carring either the MYH7 or MYBPC3 variant in isolation (Richard 1999). It has also been identified in 2/129164 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID# 14119). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PS4_Supporting, PP1. -
Likely pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 08, 2024This missense variant replaces glutamic acid with lysine at codon 483 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least six unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 10424815, 12797239, 24111713, 24704860, 25351510, 27532257, 28378410, 33495596, 33495597). It has been shown that this variant segregates with disease in multiple individuals from one family (PMID: 10424815). Some of these individuals also carried a pathogenic variant in the MYBPC3 gene that could explain the observation of a more severely affected phenotype (PMID: 10424815). This variant has been identified in 2/282856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 07, 2021Variant summary: MYH7 c.1447G>A (p.Glu483Lys) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes (gnomAD). c.1447G>A has been reported in the literature in multiple individuals affected with Cardiomyopathy (examples: Richard_1999, Berge_2013 and Walsh_2017) . These data indicate that the variant is associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJan 17, 2023- -
MYH7-related skeletal myopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJul 28, 2023Reported in association with HCM in published literature (PMID: 24111713, 10424815, 12707239, 25351510, 27532257, 35653365); Identified in several individuals with HCM from a single large family; a few individuals also have a pathogenic nonsense variant in the MYBPC3 gene and the individuals with both variants were described as showing a greater degree of hypertrophy than those with only one variant (PMID: 10424815, 12707239); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22874472, 34495297, 35753512, 12110947, 28606303, 18761664, 35653365, 25351510, 12707239, 27532257, 29300372, 10424815, 24111713) -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 28, 2024The p.E483K pathogenic mutation (also known as c.1447G>A), located in coding exon 13 of the MYH7 gene, results from a G to A substitution at nucleotide position 1447. The glutamic acid at codon 483 is replaced by lysine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant was detected in a family with hypertrophic cardiomyopathy (HCM) where it occurred alone in four affected individuals and co-occurred with an MYBPC3 alteration in two affected individuals with more significant hypertrophy (Richard P et al. J. Med. Genet., 1999 Jul;36:542-5). This variant has also been detected in multiple additional individuals from HCM cohorts (Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.4
D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.013
D
Polyphen
0.58
P
Vest4
0.99
MutPred
0.83
Gain of catalytic residue at I478 (P = 0.0075);
MVP
1.0
MPC
2.2
ClinPred
0.99
D
GERP RS
4.2
Varity_R
0.84
gMVP
1.0

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.

Other links and lift over

dbSNP: rs121913651; hg19: chr14-23897840; COSMIC: COSV100806385; API