VCV000181136.18 - ClinVar

NM_000256.3(MYBPC3):c.3713T>C (p.Leu1238Pro)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic
Likely pathogenic (5)

5 out of 5 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.3713T>C (p.Leu1238Pro)

Variation ID: 181136 Accession: VCV000181136.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332173 (GRCh38) [ NCBI UCSC ] 11: 47353724 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Aug 4, 2026	Aug 6, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

L1238P

Other names

p.L1238P:CTG>CCG

Canonical SPDI

NC_000011.10:47332172:A:G

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA014684 dbSNP: rs730880702 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
MYBPC3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4724	4746

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 Help 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.
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 13, 2017	RCV000158461.3
Hypertrophic cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Feb 19, 2025	RCV000459464.12
Hypertrophic cardiomyopathy 4	Likely pathogenic (1)	criteria provided, single submitter	Aug 6, 2025	RCV001808429.4
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Nov 6, 2024	RCV003372628.3

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Feb 13, 2017) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000208396.9 First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Nov 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004081784.3 First in ClinVar: Oct 28, 2023 Last updated: Jan 13, 2025	Publications: PubMed (7) PubMed: 20641121‚ 24111713‚ 27532257‚ 28971120‚ 30665703‚ 32841044‚ 35653365 Comment: show 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Feb 19, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000546430.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 20641121‚ 24111713‚ 27532257‚ 28492532‚ 32841044‚ 35653365 Comment: show 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; internal data). 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Jan 26, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000924852.2 First in ClinVar: Jun 29, 2019 Last updated: Aug 04, 2026	Observation: 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown Observation 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown

Likely pathogenic (Aug 06, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	3billion Accession: SCV002058124.2 First in ClinVar: Jan 15, 2022 Last updated: Jun 20, 2026	Publications: PubMed (1) PubMed: 20641121 Comment: show The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181136 /PMID: 20641121 /3billion dataset). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 20641121). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Platform type: exome sequencing

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 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.

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 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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). 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; internal data). 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.

Comment:

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181136 /PMID: 20641121 /3billion dataset). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 20641121). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Aug 04, 2026