ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.4135G>A (p.Ala1379Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000257.4(MYH7):c.4135G>A (p.Ala1379Thr)
Variation ID: 42993 Accession: VCV000042993.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23418244 (GRCh38) [ NCBI UCSC ] 14: 23887453 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 7, 2014 Feb 14, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.4135G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Ala1379Thr missense NC_000014.9:g.23418244C>T NC_000014.8:g.23887453C>T NG_007884.1:g.22418G>A LRG_384:g.22418G>A LRG_384t1:c.4135G>A P12883:p.Ala1379Thr - Protein change
- A1379T
- Other names
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- Canonical SPDI
- NC_000014.9:23418243:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MYH7 | No evidence available | No evidence available |
GRCh38 GRCh37 |
3417 | 4600 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Jan 27, 2020 | RCV000035887.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 18, 2016 | RCV000162337.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 23, 2023 | RCV000505712.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2023 | RCV000619392.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000629005.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 20, 2021 | RCV003149622.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Feb 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 1
Affected status: yes
Allele origin:
germline
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Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000299237.1
First in ClinVar: Sep 09, 2016 Last updated: Sep 09, 2016 |
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Pathogenic
(Jan 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001337987.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Comment:
Variant summary: MYH7 c.4135G>A (p.Ala1379Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five … (more)
Variant summary: MYH7 c.4135G>A (p.Ala1379Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes (gnomAD). c.4135G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Richard_2003, Blair_2002, Ross_2017). Blair_2002 reported that this variant segregated with disease in three unrelated families and was not present in 200 control chromosomes. These data indicate that the variant is very likely to be associated with disease. At least one publication, Flashman_2007, reports this variant has no effect on interaction with C10 of cMyBP-C. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838748.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000737001.5
First in ClinVar: Apr 14, 2018 Last updated: Apr 15, 2023 |
Comment:
The p.A1379T pathogenic mutation (also known as c.4135G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at … (more)
The p.A1379T pathogenic mutation (also known as c.4135G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4135. The alanine at codon 1379 is replaced by threonine, an amino acid with some similar properties. This variant was reported to segregate with hypertrophic cardiomyopathy (HCM) or related features in multiple individuals across three HCM proband-identified families, and has also been detected in additional HCM cohorts (Blair E et al. Circ Res. 2002;90:263-9; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Richard P et al. Circulation. 2003;107:2227-32; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Aug 23, 2013)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059538.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Ala1379Thr variant in MYH7 has been reported in 5 families with HCM, segre gated with disease in >15 affected relatives from 4 families (Blair … (more)
The p.Ala1379Thr variant in MYH7 has been reported in 5 families with HCM, segre gated with disease in >15 affected relatives from 4 families (Blair 2002, Richar d 2003, Zou 2013, LMM data) and was absent from large population studies. This v ariant was predicted to be pathogenic using a computational tool clinically vali dated by our laboratory. This tool's pathogenic prediction is estimated to be co rrect 94% of the time (Jordan 2011). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon s egregation studies and absence from controls. (less)
Number of individuals with the variant: 10
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Pathogenic
(Aug 23, 2018)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000212637.2
First in ClinVar: Mar 24, 2015 Last updated: May 04, 2020 |
Comment:
MYH7 Ala1379Thr has previously been identified in multple HCM cases (Walsh R et al., 2017; Zou Y et al., 2013; Richard P et al., 2003; … (more)
MYH7 Ala1379Thr has previously been identified in multple HCM cases (Walsh R et al., 2017; Zou Y et al., 2013; Richard P et al., 2003; Blair E et al., 2002). Familial analysis by Blair E. et al. (2002) demonstrated strong segregation of this variant with disease phenotype. We have detected this variant in 4 unrelated HCM families, 3 of which were reported previously (Ingles J et al., 2017; Burns et al., 2017) and segregated to an additional 3 affected family members in one family. Furthermore, this variant is absent in both the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and 1000 genomes project (http://www.1000genomes.org/). In silico tools SIFT, MutationTaster and PolyPhen-2 predict that the variant is deleterious. More specifically, a tool designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts this MYH7 Ala1379Thr variant to be "Pathogenic". Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant has been identified in more than 10 unrelated probands (PS4_Strong), has strong segregation data (PP1_Strong), is rare in the general population (PM2) and in silico tools predict that it is deleterious (PP3), therefore we classify MYH7 Ala1379Thr as 'pathogenic'. (less)
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Pathogenic
(Jan 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000208572.8
First in ClinVar: Feb 24, 2015 Last updated: Nov 11, 2023 |
Comment:
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; … (more)
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: 25961035, 28166811, 30466861, 23283745, 16918501, 11861410, 22199023, 21310275, 12707239, 27532257, 27247418, 28790153, 28615295, 33631351, 27387980, 33673806, 32894683, 33087929, 27535533, 11861413, 26582918, 35935646, 34076677) (less)
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000749915.4
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1379 of the MYH7 protein (p.Ala1379Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1379 of the MYH7 protein (p.Ala1379Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11861413, 12707239, 23283745, 27247418, 27532257, 28790153). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42993). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 16, 2013)
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no assertion criteria provided
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000188802.1
First in ClinVar: Sep 07, 2014 Last updated: Sep 07, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing. | Burns C | Circulation. Cardiovascular genetics | 2017 | PMID: 28790153 |
Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. | Ross SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28615295 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation. | Homburger JR | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 27247418 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. | Zou Y | Molecular biology reports | 2013 | PMID: 23283745 |
Localization of the binding site of the C-terminal domain of cardiac myosin-binding protein-C on the myosin rod. | Flashman E | The Biochemical journal | 2007 | PMID: 16918501 |
Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. | Bohlega S | Neurology | 2004 | PMID: 15136674 |
Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. | Nanni L | Biochemical and biophysical research communications | 2003 | PMID: 12951062 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
Mutations of the light meromyosin domain of the beta-myosin heavy chain rod in hypertrophic cardiomyopathy. | Blair E | Circulation research | 2002 | PMID: 11861413 |
Beta-myosin heavy chain gene mutations in familial hypertrophic cardiomyopathy: the usual suspect? | McNally EM | Circulation research | 2002 | PMID: 11861410 |
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Text-mined citations for rs397516202 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.