VCV000042544.5 - ClinVar

NM_000256.3(MYBPC3):c.1535T>A (p.Leu512Gln)

Germline

Classification

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

Uncertain significance
Uncertain significance (3)

3 out of 3 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.1535T>A (p.Leu512Gln)

Variation ID: 42544 Accession: VCV000042544.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47342667 (GRCh38) [ NCBI UCSC ] 11: 47364218 (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	Jan 31, 2015	Feb 15, 2026	Sep 27, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1535T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Leu512Gln	missense
NC_000011.10:g.47342667A>T
NC_000011.9:g.47364218A>T
NG_007667.1:g.15036T>A
LRG_386:g.15036T>A
LRG_386t1:c.1535T>A	LRG_386p1:p.Leu512Gln

... more HGVS ... less HGVS

Protein change

L512Q

Other names

Canonical SPDI

NC_000011.10:47342666:A:T

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.

Links

ClinGen: CA010574 dbSNP: rs397515909 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	4728	4750

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 specified	Uncertain significance (1)	criteria provided, single submitter	Apr 7, 2011	RCV000035410.5
Hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Sep 27, 2025	RCV006461246.1
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 2, 2025	RCV006547518.1

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.	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.
Uncertain significance (Sep 27, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV007374607.1 First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026	Publications: PubMed (1) PubMed: 27532257 Comment: show This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 512 of the MYBPC3 protein (p.Leu512Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42544). 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Apr 07, 2011) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059058.5 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Comment: show Variant classified as Uncertain Significance - Favor Pathogenic. The Leu512Gln v ariant has not been reported in the literature and has not been previously detec ted in >1,600 Caucasian probands tested by our laboratory. This individual?s rac ial background is reported to be Caucasian and the low frequency of the Leu512Gl n variant in this population supports a pathogenic role. Leucine (Leu) at positi on 512 is highly conserved across several evolutionary distant species, increasi ng the likelihood that the change is pathogenic. However, in the absence of addi tional supporting data (segregation and control studies), the clinical significa nce of this variant cannot be determined at this time. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Uncertain significance (Jul 02, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV007439953.1 First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 25611685‚ 27532257 Comment: show This missense variant replaces leucine with glutamine at codon 512 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. 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: 25611685, 27532257). This variant has not been identified 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 512 of the MYBPC3 protein (p.Leu512Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42544). 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:

Variant classified as Uncertain Significance - Favor Pathogenic. The Leu512Gln v ariant has not been reported in the literature and has not been previously detec ted in >1,600 Caucasian probands tested by our laboratory. This individual?s rac ial background is reported to be Caucasian and the low frequency of the Leu512Gl n variant in this population supports a pathogenic role. Leucine (Leu) at positi on 512 is highly conserved across several evolutionary distant species, increasi ng the likelihood that the change is pathogenic. However, in the absence of addi tional supporting data (segregation and control studies), the clinical significa nce of this variant cannot be determined at this time.

Comment:

This missense variant replaces leucine with glutamine at codon 512 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. 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: 25611685, 27532257). This variant has not been identified 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685

Text-mined citations for rs397515909 ...

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 Feb 15, 2026