VCV000454326.24 - ClinVar

NM_000256.3(MYBPC3):c.3358C>T (p.Arg1120Cys)

Germline

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.

(11)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.3358C>T (p.Arg1120Cys)

Variation ID: 454326 Accession: VCV000454326.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332946 (GRCh38) [ NCBI UCSC ] 11: 47354497 (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	Apr 9, 2018	Jul 23, 2024	May 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3358C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Arg1120Cys	missense
NC_000011.10:g.47332946G>A
NC_000011.9:g.47354497G>A
NG_007667.1:g.24757C>T
LRG_386:g.24757C>T
LRG_386t1:c.3358C>T	LRG_386p1:p.Arg1120Cys

... more HGVS ... less HGVS

Protein change

R1120C

Other names

Canonical SPDI

NC_000011.10:47332945:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA053677 dbSNP: rs368721523 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	3971	3990

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.
Hypertrophic cardiomyopathy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Dec 6, 2023	RCV000547056.12
Hypertrophic cardiomyopathy 4	Uncertain significance (2)	criteria provided, single submitter	Sep 21, 2015	RCV000601241.2
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Apr 24, 2023	RCV001188388.4
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	May 14, 2024	RCV001564894.9
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Nov 8, 2018	RCV002323907.2
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Sep 7, 2021	RCV002490930.1

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.
Uncertain significance (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000745029.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Center for Human Genetics, University of Leuven Accession: SCV000886825.1 First in ClinVar: May 02, 2019 Last updated: May 02, 2019
Uncertain significance (Sep 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002786290.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Dec 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003817150.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Apr 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001355444.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 30528150‚ 31514951 Comment: This missense variant replaces arginine with cysteine at codon 1120 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with cysteine at codon 1120 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30528150) and in an individual affected with dilated cardiomyopathy (PMID: 31514951). This variant has been identified in 7/241840 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)
Uncertain significance (Dec 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000623591.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 28492532‚ 30528150‚ 31514951 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1120 of the MYBPC3 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1120 of the MYBPC3 protein (p.Arg1120Cys). This variant is present in population databases (rs368721523, gnomAD 0.01%). This missense change has been observed in individuals with documented episodes of atrioventricular block (PMID: 30528150, 31514951). ClinVar contains an entry for this variant (Variation ID: 454326). 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)
Uncertain Significance (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004836613.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (2) PubMed: 30528150‚ 31514951 Comment: This missense variant replaces arginine with cysteine at codon 1120 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with cysteine at codon 1120 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30528150) and in an individual affected with dilated cardiomyopathy (PMID: 31514951). This variant has been identified in 7/241840 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: 8
Uncertain significance (Nov 08, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002607177.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.R1120C variant (also known as c.3358C>T), located in coding exon 31 of the MYBPC3 gene, results from a C to T substitution at nucleotide … (more) The p.R1120C variant (also known as c.3358C>T), located in coding exon 31 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3358. The arginine at codon 1120 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (May 14, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001788134.2 First in ClinVar: Aug 19, 2021 Last updated: Jul 23, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has been reported in association with HCM in published literature … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has been reported in association with HCM in published literature (PMID: 31513939, 31514951, 30528150); This variant is associated with the following publications: (PMID: 31514951, 30528150, 31513939) (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733028.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034685.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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Comment:

This missense variant replaces arginine with cysteine at codon 1120 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30528150) and in an individual affected with dilated cardiomyopathy (PMID: 31514951). This variant has been identified in 7/241840 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.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1120 of the MYBPC3 protein (p.Arg1120Cys). This variant is present in population databases (rs368721523, gnomAD 0.01%). This missense change has been observed in individuals with documented episodes of atrioventricular block (PMID: 30528150, 31514951). ClinVar contains an entry for this variant (Variation ID: 454326). 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.

Comment:

The p.R1120C variant (also known as c.3358C>T), located in coding exon 31 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3358. The arginine at codon 1120 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has been reported in association with HCM in published literature (PMID: 31513939, 31514951, 30528150); This variant is associated with the following publications: (PMID: 31514951, 30528150, 31513939)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy.	Gigli M	Journal of the American College of Cardiology	2019	PMID: 31514951
High-degree atrioventricular block revealing hypertrophic cardiomyopathy related to a mutation in MYBPC3 gene.	Kouakam C	Presse medicale (Paris, France : 1983)	2019	PMID: 30528150

Text-mined citations for rs368721523 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000256.3(MYBPC3):c.3358C>T (p.Arg1120Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs368721523 ...