ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.1219G>A (p.Gly407Ser)
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_000256.3(MYBPC3):c.1219G>A (p.Gly407Ser)
Variation ID: 179988 Accession: VCV000179988.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47343496 (GRCh38) [ NCBI UCSC ] 11: 47365047 (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 Jun 1, 2016 May 1, 2024 Nov 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.1219G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Gly407Ser missense NC_000011.10:g.47343496C>T NC_000011.9:g.47365047C>T NG_007667.1:g.14207G>A LRG_386:g.14207G>A LRG_386t1:c.1219G>A LRG_386p1:p.Gly407Ser - Protein change
- G407S
- Other names
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- Canonical SPDI
- NC_000011.10:47343495: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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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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MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3901 | 3920 |
Conditions - Germline
Condition
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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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 23, 2023 | RCV000156791.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2019 | RCV000992420.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 22, 2023 | RCV000466322.5 | |
MYBPC3-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 8, 2023 | RCV004551350.2 |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 7, 2021 | RCV002362833.2 |
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
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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
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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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Uncertain significance
(Dec 28, 2018)
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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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Athena Diagnostics
Accession: SCV001144701.1
First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020 |
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Uncertain significance
(May 23, 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: SCV003934387.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: MYBPC3 c.1219G>A (p.Gly407Ser) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Three … (more)
Variant summary: MYBPC3 c.1219G>A (p.Gly407Ser) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 210360 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1219G>A has been reported in the literature in an individual affected with Dilated Cardiomyopathy (Waldmuller_2011). This report does 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 publication have been ascertained in the context of this evaluation (PMID: 21750094). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jan 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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MYBPC3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115635.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MYBPC3 c.1219G>A variant is predicted to result in the amino acid substitution p.Gly407Ser. This variant was reported in one individual with dilated cardiomyopathy; however, … (more)
The MYBPC3 c.1219G>A variant is predicted to result in the amino acid substitution p.Gly407Ser. This variant was reported in one individual with dilated cardiomyopathy; however, further clinical details were not provided (Supplementary Table 2, Waldmüller et al 2011. PubMed ID: 21750094). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, other variants at the same amino acid (p.Gly407Arg and p.Gly407Asp) have been reported in patients with MYBPC3-related disease (Coban-Akdemir et al. 2020. PubMed ID: 32233023; Supplementary Table 1, Wang et al. 2014. PubMed ID: 25132132). Although we suspect that the c.1219G>A (p.Gly407Ser) variant could be pathogenic, at this time, we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Nov 22, 2023)
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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: SCV000546405.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 407 of the MYBPC3 protein (p.Gly407Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 407 of the MYBPC3 protein (p.Gly407Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 21750094). ClinVar contains an entry for this variant (Variation ID: 179988). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Apr 04, 2019)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000206512.5
First in ClinVar: Jan 31, 2015 Last updated: Apr 20, 2024 |
Comment:
The p.Gly407Ser variant in MYBPC3 has been reported in 1 German individual with DCM (Waldmuller 2011). It was absent from large population studies. Computational prediction … (more)
The p.Gly407Ser variant in MYBPC3 has been reported in 1 German individual with DCM (Waldmuller 2011). It was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Gly407Ser variant is uncertain. (less)
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Uncertain significance
(Dec 07, 2021)
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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: SCV002656437.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G407S variant (also known as c.1219G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide … (more)
The p.G407S variant (also known as c.1219G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1219. The glycine at codon 407 is replaced by serine, an amino acid with similar properties. This variant has been detected in a dilated cardiomyopathy cohort; however, details were limited (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Sep 01, 2014)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280206.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly407Ser (c.1219 G>A) in MYBPC3 Based on the data reviewed below we consider this variant a variant of uncertain significance, likely disease causing. The variant has been seen in at least one unrelated cases of DCM with no segregation data. Waldmuller et al (2011) sequenced MYH7 and MYBPC3 in 652 patients with DCM from a multi-center German cohort and identified this variant in one patient. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The glycine at codon 407 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (p.Ser408Asn, p.Gly416Ser). This substitution occurs 5 nucleotides from the end of exon 13, thus it is possible that the variant impacts splicing. I emailed GeneDx to ask what their in silico splicing prediction programs predict and they told me that the two algorithms they ran predict no impact on splicing. In total the variant has not been seen in ~6500 from publicly available population datasets. There is no variation at codon 407 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of March 8th, 2013). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of March 8 th, 2013). (less)
Number of individuals with the variant: 2
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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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Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. | Wang J | European journal of heart failure | 2014 | PMID: 25132132 |
Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. | Waldmüller S | European journal of heart failure | 2011 | PMID: 21750094 |
Text-mined citations for rs727505266 ...
HelpRecord last updated Jun 30, 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.