ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.2783C>T (p.Ser928Leu)
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.2783C>T (p.Ser928Leu)
Variation ID: 427958 Accession: VCV000427958.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47335164 (GRCh38) [ NCBI UCSC ] 11: 47356715 (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 Aug 20, 2017 Apr 20, 2024 Nov 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.2783C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Ser928Leu missense NC_000011.10:g.47335164G>A NC_000011.9:g.47356715G>A NG_007667.1:g.22539C>T LRG_386:g.22539C>T LRG_386t1:c.2783C>T LRG_386p1:p.Ser928Leu - Protein change
- S928L
- Other names
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- Canonical SPDI
- NC_000011.10:47335163:G:A
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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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
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
Help
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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MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3858 | 3875 |
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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Uncertain significance (4) |
criteria provided, single submitter
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Sep 21, 2022 | RCV000498497.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 30, 2017 | RCV000498962.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2023 | RCV000799722.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001104920.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 16, 2023 | RCV001179576.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 12, 2019 | RCV001193932.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001104921.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 18, 2023 | RCV002438198.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 11, 2021 | RCV002481558.1 |
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
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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Uncertain significance
(Apr 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Prolonged QT interval
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, University of Leuven
Accession: SCV000579549.1
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Secondary finding: yes
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001261826.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001261827.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Feb 12, 2019)
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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: SCV001363109.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MYBPC3 c.2783C>T (p.Ser928Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain of the encoded protein sequence. Three … (more)
Variant summary: MYBPC3 c.2783C>T (p.Ser928Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 244814 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2783C>T has been reported in the literature in affected individuals (Berge_2014, Brito_2012, Brito_2005). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.2373dupG, p.W792VfsX41; MYH7 c.788T>C, p.Ile263Thr) (Berge_2014, Brito_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Oct 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002791300.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Aug 23, 2022)
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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: SCV000939398.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 928 of the MYBPC3 protein (p.Ser928Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 928 of the MYBPC3 protein (p.Ser928Leu). 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: 16335287, 22857948, 24111713, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 427958). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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
(Sep 21, 2022)
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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: SCV000589344.5
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
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: 24111713, … (more)
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: 24111713, 22857948, 25214167, 33782553, 29853478, 31323898, 32369506, 16335287, 30847666) (less)
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Uncertain significance
(Apr 18, 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: SCV002748256.2
First in ClinVar: Nov 29, 2022 Last updated: Jul 08, 2023 |
Comment:
The p.S928L variant (also known as c.2783C>T), located in coding exon 27 of the MYBPC3 gene, results from a C to T substitution at nucleotide … (more)
The p.S928L variant (also known as c.2783C>T), located in coding exon 27 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2783. The serine at codon 928 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts and individuals with HCM; however, it co-occurred with pathogenic mutations in cardiomyopathy-related genes in at least two cases, and cohort reports may overlap (Brito D et al. Rev Port Cardiol, 2005 Sep;24:1137-46; Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Nijenkamp LLAM et al. Circ Heart Fail. 2018 06;11(6):e004133; Helms AS et al. Circ Genom Precis Med. 2020 Oct;13(5):396-405; Harper AR et al. Nat Genet. 2021 Feb;53(2):135-142). This variant has also been detected in an individual reported to have long QT syndrome, and in an individual who underwent genetic testing for dilated cardiomyopathy; however, clinical details were limited (Robyns T et al. Eur. J. Hum. Genet. 2017 12;25(12):1313-1323; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well 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
(Mar 16, 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: SCV001344270.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with leucine at codon 928 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with leucine at codon 928 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 22857948, 31323898). One of these individuals also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 22857948). This variant has been identified in 6/247572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004836715.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces serine with leucine at codon 928 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with leucine at codon 928 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 22857948, 31323898). One of these individuals also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 22857948). This variant has been identified in 6/247572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 6
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920330.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931459.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957873.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation. | Thompson AD | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33782553 |
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. | Helms AS | Circulation. Genomic and precision medicine | 2020 | PMID: 32841044 |
Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy. | Dorsch LM | Cells | 2019 | PMID: 31323898 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Sex Differences at the Time of Myectomy in Hypertrophic Cardiomyopathy. | Nijenkamp LLAM | Circulation. Heart failure | 2018 | PMID: 29853478 |
Repeat genetic testing with targeted capture sequencing in primary arrhythmia syndrome and cardiomyopathy. | Robyns T | European journal of human genetics : EJHG | 2017 | PMID: 29255176 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
Sarcomeric hypertrophic cardiomyopathy: genetic profile in a Portuguese population. | Brito D | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2012 | PMID: 22857948 |
Malignant mutations in hypertrophic cardiomyopathy: fact or fancy? | Brito D | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2005 | PMID: 16335287 |
Text-mined citations for rs773819168 ...
HelpRecord last updated Apr 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.