ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3713T>C (p.Leu1238Pro)
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.3713T>C (p.Leu1238Pro)
Variation ID: 181136 Accession: VCV000181136.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47332173 (GRCh38) [ NCBI UCSC ] 11: 47353724 (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 24, 2015 May 1, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3713T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Leu1238Pro missense NC_000011.10:g.47332173A>G NC_000011.9:g.47353724A>G NG_007667.1:g.25530T>C LRG_386:g.25530T>C LRG_386t1:c.3713T>C LRG_386p1:p.Leu1238Pro - Protein change
- L1238P
- Other names
- p.L1238P:CTG>CCG
- Canonical SPDI
- NC_000011.10:47332172:A:G
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 |
3890 | 3907 |
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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Likely pathogenic (2) |
criteria provided, single submitter
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Feb 13, 2017 | RCV000158461.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 19, 2024 | RCV000459464.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV001808429.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV003372628.2 |
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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Likely pathogenic
(Feb 13, 2017)
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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: SCV000208396.9
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
The L1238P variant in the MYBPC3 gene has been reported in two probands with HCM (Choi et al., 2010; Berge et al., 2014). The variant … (more)
The L1238P variant in the MYBPC3 gene has been reported in two probands with HCM (Choi et al., 2010; Berge et al., 2014). The variant segregated with HCM in 5 relatives of one affected proband (Choi et al., 2010). The L1238P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L1238P variant is a semiconservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. (less)
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Likely pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058124.1
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: VCV000181136, PMID:20641121, PS1_S). In … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181136, PMID:20641121, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96, 3CNET: 0.996, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present)
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Likely pathogenic
(Jan 19, 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: SCV000546430.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1238 of the MYBPC3 protein (p.Leu1238Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1238 of the MYBPC3 protein (p.Leu1238Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20641121, 24111713, 27532257, 32841044, 35653365; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181136). 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. Studies have shown that this missense change alters MYBPC3 gene expression (PMID: 32841044). 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
(Aug 22, 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: SCV004081784.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The p.L1238P variant (also known as c.3713T>C), located in coding exon 33 of the MYBPC3 gene, results from a T to C substitution at nucleotide … (more)
The p.L1238P variant (also known as c.3713T>C), located in coding exon 33 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 3713. The leucine at codon 1238 is replaced by proline, an amino acid with similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and has been noted to segregate with disease (Choi JO et al. Clin Cardiol, 2010 Jul;33:430-8; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Wright CF et al. Am J Hum Genet, 2019 Feb;104:275-286; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Jan 26, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924852.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
Testing was performed at GeneDx. Given the moderate case data, segregation at least 4 individuals in one family, and absence in population databases, we consider … (more)
Testing was performed at GeneDx. Given the moderate case data, segregation at least 4 individuals in one family, and absence in population databases, we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Pursuing additional segregation studies in other affected family members could strengthen the segregation data for this variant. The variant has been seen in at least 4 unrelated individuals with HCM (not including this patient's family). There is mild segregation data from the one family reported in the literature. A different genetic testing laboratory noted that they have seen this variant in one individual with HCM. Choi et al. 2010 report a Korean family in which 4 individuals with HCM carry this variant. Below is a pedigree for reference. Of note, the paper does not indicate how these patients were tested for genetic variants and do not list which genes were included in the original genetic testing. II-3 was 63yo at last follow up had an IVSd measuring 2.9cm, had NSVT on Holter and has an ICD. He had an EF of 70% and MRI showed areas of delayed enhancement. III-2 has HCM dx at age 40 with an IVSd 2.3cm, EF of 30%, apical thrombus, LAE, and afib. She also had hypertension. III-3 has HCM dx at age 27 with history of afib and VT, IVSd measuring 2.4cm and EF of 25%. Authors note he progressed to heart failure and DCM-like phenotype. He died of intractable VT at age 54. III-5 has HCM dx at age 28 with improved EF on follow up. IVSd of 1.7cm, NSVT on Holter and EF of 39%. Authors note he was a heavy alcoholic and developed a DCM phenotype at age 31. Once he gave up alcohol his EF and LVEDD returned to normal. Berge et al (2014) reports this variant in a Norwegian proband with HCM. No specific phenotypic information is included. Genetic testing was done on a research basis and not at a known laboratory, to our knowledge. Walsh et al (2016), in collaboration with Cook, Ware, and MacArthur, report that is variant was identified in an individual with HCM. Testing was performed at Oxford Medical Genetics Laboratories. No other details are provided. The variant is not present in the SHaRe database. There is no variation at codon 1238 listed in the Exome Aggregation Consortium Dataset (ExAC; http://exac.broadinstitute.org/), which currently includes variant calls on >60,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is 70x. There is no variation at codon 1238 listed in the Genome Aggregation Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 80x for exomes and 35x for genomes. (less)
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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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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 |
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 |
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting. | Wright CF | American journal of human genetics | 2019 | PMID: 30665703 |
Data on exercise and cardiac imaging in a patient cohort with hypertrophic cardiomyopathy. | Dejgaard LA | Data in brief | 2017 | PMID: 28971120 |
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 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
Long-term outcome of 4 Korean families with hypertrophic cardiomyopathy caused by 4 different mutations. | Choi JO | Clinical cardiology | 2010 | PMID: 20641121 |
Text-mined citations for rs730880702 ...
HelpRecord last updated May 01, 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.