VCV000164159.23 - ClinVar

NM_000256.3(MYBPC3):c.74G>A (p.Ser25Asn)

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.

(12)

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.

Conflicting classifications of pathogenicity
Uncertain significance(10); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.74G>A (p.Ser25Asn)

Variation ID: 164159 Accession: VCV000164159.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47351457 (GRCh38) [ NCBI UCSC ] 11: 47373008 (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	Mar 29, 2015	Nov 17, 2024	May 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.74G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Ser25Asn	missense
NC_000011.10:g.47351457C>T
NC_000011.9:g.47373008C>T
NG_007667.1:g.6246G>A
LRG_386:g.6246G>A
LRG_386t1:c.74G>A	LRG_386p1:p.Ser25Asn

... more HGVS ... less HGVS

Protein change

S25N

Other names

Canonical SPDI

NC_000011.10:47351456:C:T

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.

0.00040 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00006

The Genome Aggregation Database (gnomAD) 0.00021

Trans-Omics for Precision Medicine (TOPMed) 0.00021

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00039

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

Links

ClinGen: CA015780 dbSNP: rs371140684 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.
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 29, 2019	RCV000151173.7
Hypertrophic cardiomyopathy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Dec 13, 2023	RCV000314127.15
Left ventricular noncompaction cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000350432.5
Dilated Cardiomyopathy, Dominant	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000402678.5
Cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Oct 19, 2021	RCV001170432.3
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 9, 2024	RCV003129791.4
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Mar 30, 2021	RCV003224173.1
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Sep 5, 2021	RCV002390324.2

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 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 (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Dilated Cardiomyopathy, Dominant Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372419.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Left Ventricular Noncompaction Cardiomyopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372421.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Hypertrophic Cardiomyopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372420.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Oct 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333011.2 First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Uncertain significance (Sep 18, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198991.4 First in ClinVar: Jan 30, 2015 Last updated: Mar 29, 2015	Comment: Variant classified as Uncertain Significance - Favor Benign. The Ser25Asn varian t in MYBPC3 as not been previously reported in individuals with cardiomyopathy b ut … (more) Variant classified as Uncertain Significance - Favor Benign. The Ser25Asn varian t in MYBPC3 as not been previously reported in individuals with cardiomyopathy b ut has been identified in 0.1% (5/4232) of African American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs371140 684). Serine (Ser) at position 25 is not conserved in evolution with 2 species ( 1 mammal, 1 bird) carrying the variant amino acid, suggesting that this change m ay be tolerated. The change was also predicted to be benign using a computationa l tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). Although this data suppor ts that the Ser25Asn variant may be benign, additional studies are needed to ful ly assess its clinical significance. (less) Number of individuals with the variant: 1
Uncertain significance (Oct 29, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001363320.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (1) PubMed: 24510615 Comment: Variant summary: MYBPC3 c.74G>A (p.Ser25Asn) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain of the encoded protein sequence. Four … (more) Variant summary: MYBPC3 c.74G>A (p.Ser25Asn) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 237812 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (4.2e-05 vs 0.001), allowing no conclusion about variant significance. c.74G>A has not been reported in the literature in individuals affected with Cardiomyopathy nor has experimental evidence demonstrating an impact on protein function been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10 Left ventricular noncompaction 10 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920225.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: MYBPC3 NM_000256.3 exon 2 p.Ser25Asn (c.74G>A): This variant has not been reported in the literature but is present in 0.07% (17/22832) of African alleles in … (more) MYBPC3 NM_000256.3 exon 2 p.Ser25Asn (c.74G>A): This variant has not been reported in the literature but is present in 0.07% (17/22832) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-47373008-C-T) and is present in ClinVar (Variation ID:164159). This variant amino acid (Asn) is present in several species including some mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Uncertain significance (Jun 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003817157.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Dec 11, 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: SCV000623619.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Comment: This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 25 of the MYBPC3 protein (p.Ser25Asn). … (more) This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 25 of the MYBPC3 protein (p.Ser25Asn). This variant is present in population databases (rs371140684, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 164159). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 13, 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: SCV004845003.1 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)	Comment: This missense variant replaces serine with asparagine at codon 25 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces serine with asparagine at codon 25 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 17/269206 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: 7
Likely benign (Sep 05, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002672565.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 24510615‚ 30847666 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (May 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005396487.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Comment: Identified in a patient with HCM in published literature; this patient harbored additional cardiogenetic variants (PMID: 30847666); In silico analysis indicates that this missense variant … (more) Identified in a patient with HCM in published literature; this patient harbored additional cardiogenetic variants (PMID: 30847666); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24510615, 30847666) (less)
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Comment:

Variant classified as Uncertain Significance - Favor Benign. The Ser25Asn varian t in MYBPC3 as not been previously reported in individuals with cardiomyopathy b ut has been identified in 0.1% (5/4232) of African American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs371140 684). Serine (Ser) at position 25 is not conserved in evolution with 2 species ( 1 mammal, 1 bird) carrying the variant amino acid, suggesting that this change m ay be tolerated. The change was also predicted to be benign using a computationa l tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). Although this data suppor ts that the Ser25Asn variant may be benign, additional studies are needed to ful ly assess its clinical significance.

Comment:

Variant summary: MYBPC3 c.74G>A (p.Ser25Asn) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 237812 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (4.2e-05 vs 0.001), allowing no conclusion about variant significance. c.74G>A has not been reported in the literature in individuals affected with Cardiomyopathy nor has experimental evidence demonstrating an impact on protein function been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

MYBPC3 NM_000256.3 exon 2 p.Ser25Asn (c.74G>A): This variant has not been reported in the literature but is present in 0.07% (17/22832) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-47373008-C-T) and is present in ClinVar (Variation ID:164159). This variant amino acid (Asn) is present in several species including some mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Comment:

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 25 of the MYBPC3 protein (p.Ser25Asn). This variant is present in population databases (rs371140684, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 164159). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:

This missense variant replaces serine with asparagine at codon 25 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 17/269206 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 alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Identified in a patient with HCM in published literature; this patient harbored additional cardiogenetic variants (PMID: 30847666); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24510615, 30847666)

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
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise.	Kapplinger JD	Journal of cardiovascular translational research	2014	PMID: 24510615

Text-mined citations for rs371140684 ...

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 Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000256.3(MYBPC3):c.74G>A (p.Ser25Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs371140684 ...