ClinVar Genomic variation as it relates to human health
NM_000257.4(MYH7):c.2348G>A (p.Arg783His)
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.
Pathogenic(1); Likely pathogenic(7); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000257.4(MYH7):c.2348G>A (p.Arg783His)
Variation ID: 180437 Accession: VCV000180437.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q11.2 14: 23425357 (GRCh38) [ NCBI UCSC ] 14: 23894566 (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 Feb 27, 2016 Oct 20, 2024 May 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000257.4:c.2348G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000248.2:p.Arg783His missense NC_000014.9:g.23425357C>T NC_000014.8:g.23894566C>T NG_007884.1:g.15305G>A LRG_384:g.15305G>A LRG_384t1:c.2348G>A - Protein change
- R783H
- Other names
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- Canonical SPDI
- NC_000014.9:23425356: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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
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
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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 |
3634 | 4908 | |
LOC126861898 | - | - | - | GRCh38 | - | 371 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2023 | RCV000157359.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 17, 2024 | RCV000618642.5 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Mar 11, 2024 | RCV000444026.31 | |
Uncertain significance (1) |
criteria provided, multiple submitters, no conflicts
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May 5, 2023 | RCV000455847.5 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV001220856.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV001808427.1 |
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
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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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Pathogenic
(Jan 03, 2022)
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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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3billion
Accession: SCV002058663.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000180437, PMID:18258667, PS1_S). A … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000180437, PMID:18258667, PS1_S). A different missense change at the same codon (p.Arg783Pro, p.Arg783Gly) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042895,VCV000164335, PMID:21211974, PMID:27247418, PM5_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000021, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present)
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Uncertain significance
(Jul 29, 2021)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501664.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
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Uncertain significance
(May 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934392.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: MYH7 c.2348G>A (p.Arg783His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: MYH7 c.2348G>A (p.Arg783His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2348G>A has been reported in the literature in individuals affected with Cardiomyopathy and some publications classified this variant as pathogenic or likely pathogenic, however strong evidence for causality such as co-segregation information was not specified (examples: Lopes_2013, Walsh_2017, Sahlin_2018, Shanks_2018, Marschall_2019, Hathaway_2021, Park_2022, Sepp_2022, and Stava_2022). In two of these cases authors reported evidence of TTN variants as co-occurrences where authors classified the TTN variant as likely pathogenic (example: Shanks_2018 and Zhu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33673806, 31737537, 34542152, 35626289, 29915097, 35653365, 18258667, 27532257, 35063694, 25351510, 30615648). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=5) and VUS (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Sep 22, 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: SCV000513803.3
First in ClinVar: Mar 08, 2017 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18258667, 27532257, 24111713, 25351510, 27662471, 28831623, 29915097, 28606303, 31737537, 33673806, Farn2021[CaseReport], 35653365, 34542152, 35063694, 35626289, 35456187, 29300372, 30615648, 35534676, 34621001, 30775854) (less)
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Likely pathogenic
(Jan 08, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001392868.6
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 783 of the MYH7 protein (p.Arg783His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 783 of the MYH7 protein (p.Arg783His). This variant is present in population databases (rs397516142, gnomAD 0.004%). This missense change has been observed in individual(s) with Hypertrophic cardiomyopathy (PMID: 18258667, 24111713, 25351510, 27532257, 27662471, 33673806, 35626289; Invitae). ClinVar contains an entry for this variant (Variation ID: 180437). 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%. This variant disrupts the p.Arg783 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21211974). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely Pathogenic
(Dec 09, 2019)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539835.2
First in ClinVar: Apr 09, 2017 Last updated: Apr 20, 2024 |
Comment:
The p.Arg783His variant in MYH7 has been identified in at least 10 individuals with HCM (Berge 2014, Waldmuller 2008, Walsh 2016) and 1 individual with … (more)
The p.Arg783His variant in MYH7 has been identified in at least 10 individuals with HCM (Berge 2014, Waldmuller 2008, Walsh 2016) and 1 individual with sudden cardiac death who also carried a frameshift variant in TTN (Shanks 2018). It has been reported in 4/129170 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar (Variation ID: 180437). Of note, 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 addition, several other variants involving this codon, p.Arg783Cys, p.Arg783Pro, and p.Arg783Gly, have also been identified in individuals with cardiomyopathy. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PS4_Moderate, PM5_Supporting, BP4. (less)
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Likely pathogenic
(May 17, 2024)
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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: SCV000740110.7
First in ClinVar: Apr 14, 2018 Last updated: Aug 11, 2024 |
Comment:
The p.R783H variant (also known as c.2348G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide … (more)
The p.R783H variant (also known as c.2348G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide position 2348. The arginine at codon 783 is replaced by histidine, an amino acid with highly 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 alteration has been reported in numerous individual from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing (Waldmüller S et al. Clin. Chem., 2008 Apr;54:682-7; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Jääskeläinen P et al. ESC Heart Fail. 2019 Apr;6(2):436-445; Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126; Phan PD et al. JRSM Cardiovasc Dis. 2024 Jan;13:20480040231220100; Ambry internal data). This variant has also been reported in a subject with restrictive cardiomyopathy whose son had HCM with restrictive features (Kostareva A et al. PLoS ONE., 2016 Sep;11(9):e0163362). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Mar 11, 2024)
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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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199397.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Likely pathogenic
(May 12, 2015)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Variant found in one individual
(more...)
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000207097.3
First in ClinVar: Feb 07, 2015 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 2
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Uncertain significance
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236710.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Oct 04, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004356921.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 783 of the myosin head/motor (S1) domain of the MYH7 protein. This variant is found within … (more)
This missense variant replaces arginine with histidine at codon 783 of the myosin head/motor (S1) domain of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18258667, 24111713, 27662471, 27532257, 30775854), and in 3 individuals suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806). It has also been reported in an individual affected with primary fibrotic atrial cardiomyopathy (PMID: 35063694), in a case of stillbirth (PMID: 30615648), and in an individual affected with sudden unexplained death (PMID: 29915097). A different variant affecting the same codon, p.Arg783Pro, is considered to be disease-causing (ClinVar variation ID: 42895), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 6/282860 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Sep 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248600.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
MYH7: PM1, PM2, PS4:Moderate
Number of individuals with the variant: 5
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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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Electrocardiographic and genetic characteristics in first degree relatives of hypertrophic cardiomyopathy probands: A descriptive cross-sectional study from Vietnam. | Phan PD | JRSM cardiovascular disease | 2024 | PMID: 38186735 |
Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. | Stava TT | European journal of preventive cardiology | 2022 | PMID: 35653365 |
The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes. | Sepp R | Diagnostics (Basel, Switzerland) | 2022 | PMID: 35626289 |
Genetic Insights into Primary Restrictive Cardiomyopathy. | Brodehl A | Journal of clinical medicine | 2022 | PMID: 35456187 |
Genetic findings in patients with primary fibrotic atrial cardiomyopathy. | Zhu Y | European journal of medical genetics | 2022 | PMID: 35063694 |
Actionable secondary findings in the 73 ACMG-recommended genes in 1559 Thai exomes. | Chetruengchai W | Journal of human genetics | 2022 | PMID: 34621001 |
A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank. | Park J | Human molecular genetics | 2022 | PMID: 34542152 |
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. | Hathaway J | BMC cardiovascular disorders | 2021 | PMID: 33673806 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy. | Jääskeläinen P | ESC heart failure | 2019 | PMID: 30775854 |
Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth. | Sahlin E | PloS one | 2019 | PMID: 30615648 |
Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series. | Shanks GW | Circulation | 2018 | PMID: 29915097 |
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 |
Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing. | Kostareva A | PloS one | 2016 | PMID: 27662471 |
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 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
Novel mutation in MYH7 gene associated with distal myopathy and cardiomyopathy. | Homayoun H | Neuromuscular disorders : NMD | 2011 | PMID: 21211974 |
Array-based resequencing assay for mutations causing hypertrophic cardiomyopathy. | Waldmüller S | Clinical chemistry | 2008 | PMID: 18258667 |
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Text-mined citations for rs397516142 ...
HelpRecord last updated Oct 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.