NM_000256.3(MYBPC3):c.1624G>C (p.Glu542Gln) AND Hypertrophic cardiomyopathy 4

Germline classification:: Pathogenic (13 submissions)
Last evaluated:: Aug 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000009139.21

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1624G>C (p.Glu542Gln)]

NM_000256.3(MYBPC3):c.1624G>C (p.Glu542Gln)

Gene:

MYBPC3:myosin binding protein C3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.1624G>C (p.Glu542Gln)

Other names:

p.E542Q:GAA>CAA

HGVS:

NC_000011.10:g.47342578C>G
NG_007667.1:g.15125G>C
NM_000256.3:c.1624G>CMANE SELECT
NP_000247.2:p.Glu542Gln
LRG_386t1:c.1624G>C
LRG_386:g.15125G>C
LRG_386p1:p.Glu542Gln
NC_000011.9:g.47364129C>G
c.1624G>C
p.(Glu542Gln)/p.(Trp486*)

Protein change:

E542Q; GLU542GLN

Links:

OMIM: 600958.0006; dbSNP: rs121909374

NCBI 1000 Genomes Browser:

rs121909374

Molecular consequence:

NM_000256.3:c.1624G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy 4
Synonyms:: Familial hypertrophic cardiomyopathy 4
Identifiers:: MONDO: MONDO:0007268; MedGen: C1861862; OMIM: 115197

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000029356	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000494449	Center of Genomic medicine, Geneva, University Hospital of Geneva	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2016)	unknown	clinical testing
SCV000584103	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (HA_assertions_20150911)	Pathogenic (Dec 10, 2015)	unknown	research	HA_assertions_20150911.pdf, Citation Link,
SCV000679775	Phosphorus, Inc.	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2017)	germline	clinical testing	PubMed (36) [See all records that cite these PMIDs] 2073894, 9048664, 9631872, 10610770, 12117842, 12707239, 15519027, 16199542, 16831826, 16858239, 18414213, 18533079, 19150014, 20378854, 20433692, 20738943, 21239446, 21302287, 21835320, 21839045, 22057632, 22267749, 22765922, 23054336, 23299917, 24033266, 24093860, 24793961, 25342278, 25524337, 25611685, 25637381, 25740977, 27483260, 27532257, 25741868
SCV000993585	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI_GT	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 10, 2019)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001132521	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - CSER_ClinSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 28, 2019)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV001434956	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 30, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001468139	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	no assertion criteria provided	Pathogenic (Jun 16, 2020)	germline	clinical testing
SCV001984871	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 7, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002762765	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - HudsonAlpha-AGHI-WGS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 9, 2022)	paternal, maternal	research	PubMed (1) [See all records that cite this PMID]
SCV004040787	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004101361	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Aug 24, 2023)	unknown	clinical testing	Citation Link,
SCV004177148	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	unknown	2	not provided	not provided	2	not provided	research
not provided	paternal	unknown	1	not provided	not provided	1	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	3	not provided	not provided	3	not provided	clinical testing, research

Citations

PubMed

Local mechanical oscillations of the cell surface within the range 0.2-30 Hz.

Krol AYu, Grinfeldt MG, Levin SV, Smilgavichus AD.

Eur Biophys J. 1990;19(2):93-9.

PubMed [citation]

PMID:: 2073894

Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy.

Carrier L, Bonne G, Bährend E, Yu B, Richard P, Niel F, Hainque B, Cruaud C, Gary F, Labeit S, Bouhour JB, Dubourg O, Desnos M, Hagège AA, Trent RJ, Komajda M, Fiszman M, Schwartz K.

Circ Res. 1997 Mar;80(3):427-34.

PubMed [citation]

PMID:: 9048664

See all PubMed Citations (36)

Details of each submission

From OMIM, SCV000029356.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

The second of the 6 new mutations discovered by Carrier et al. (1997) in 7 unrelated French families with hypertrophic cardiomyopathy (CMH4; 115197) was a G-to-C transversion at position 1656 in exon 17 of the MYBPC3 gene. This was found in 2 families and produced the missense change glu542-to-gln in the C3 domain. In addition, the mutation affected the last nucleotide of the exon, which is part of the consensus splicing site. A common feature in human exon/intron boundaries is that 80% of exons finish with a guanine; this proportion is 85% in MYBPC3. As a result exon 17 was skipped. The aberrant cDNA encoded 486 normal residues, leading to a truncated protein that lacked about 62%, including the titin (188840) and myosin (160710)-binding sites.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center of Genomic medicine, Geneva, University Hospital of Geneva, SCV000494449.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000584103.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Phosphorus, Inc., SCV000679775.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (36)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI_GT, SCV000993585.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)
2	not provided	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	1	not provided	not provided		1	not provided	not provided	not provided
2	unknown	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - CSER_ClinSeq, SCV001132521.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434956.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.1624G>C (p.Glu542Gln) variant in exon 17 of the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (HCM) (PMID: 9631872, 12707239, 15519027, 16199542, 16858239, 19150014, 20738943, 21239446, 18533079, 24093860, 27483260, 27532257). It has also been reported to segregate with disease in multiple affected individuals from unrelated families (PMID: 9048664, 20433692). This variant has an extremely low frequency in general population databases. The c.1624G>C sequence change is located at the last base of the exon and predicted to alter gene splicing. mRNA studies using patient lymphocytes and cardiac tissues have confirmed that this variant causes skipping of exon 17, introducing a premature translational termination codon, while normally spliced missense transcript for c.1624G>C (p.Glu542Gln) is also expressed (PMID: 9048664, 22057632, 25031304, 28679633). Functional studies in fetal rat cardiomyocytes showed that incorporation of truncating variants of MYBPC3 into sarcomere is reduced compared to wild-type and suggested that truncating variants and the c.1624G>C (p.Glu542Gln) missense variant have a dominant negative effect on the myobrillar architecture (PMID: 10610770). In summary, this c.1624G>C (p.Glu542Gln) variant in the MYBPC3 gene is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare, SCV001468139.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001984871.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant affects the last nucleotide of exon 17 of MYBPC3 and is likely to interfere with native splicing. This variant has been previously reported mainly as a heterozygous variant in unrelated families with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), and also as a compound heterozygous change in patients with HCM (PMID: 29121657, 27532257, 31514951, 16199542, 20378854). Expression studies using mRNA from patient myocardial tissue demonstrate that this variant leads to exon skipping (PMID: 25031304) and decreased protein incorporation into the A-band of the sarcomere (PMID: 10610770). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/262678) and thus is presumed to be rare. The c.1624G>C (p.Glu542Gln) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1624G>C (p.Glu542Gln) variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - HudsonAlpha-AGHI-WGS, SCV002762765.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)
2	not provided	1	not provided	not provided	research	PubMed (1)
3	not provided	1	not provided	not provided	research	PubMed (1)

Description

ACMG codes:PVS1_VeryStrong, PS3_Supporting, PS4_Moderate, PM2_Moderate, PP1_Strong

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	unknown	1	not provided	not provided		1	not provided	not provided	not provided
2	paternal	unknown	1	not provided	not provided		1	not provided	not provided	not provided
3	maternal	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV004040787.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV004101361.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The MYBPC3 c.1624G>C (p.Glu542Gln) missense variant has been identified in individuals with hypertrophic cardiomyopathy (PMID: 9048664; 9631872; 27532257; 30645170; 36264615). This variant has been shown to segregate with disease in at least two families (PMID: 9048664). The p.Glu542Gln variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies conducted in patient cells and non-human cells demonstrate that this variant results in abnormal splicing of exon 17 leading to a truncated protein that lacks the titin and myosin binding sites (PMID: 9048664; 25031304; 30645170; 34097875). Based on the available evidence, the c.1624G>C (p.Glu542Gln) variant is classified as pathogenic for hypertrophic cardiomyopathy.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV004177148.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The MYBPC3 c.1624G>C (p.Glu542Gln) variant has been observed in individuals with hypertrophic cardiomyopathy and has been shown to segregate with disease in affected families (Carrier L et al., PMID: 9048664; Charron P et al., PMID: 9631872; Van Driest L et al., PMID: 15519027; Ingles J et al., PMID: 16199542; Olivetto I et al., PMID: 18533079; Rodríguez-García M et al., PMID: 20433692; Helms A et al., PMID: 25031304; Walsh R et al., PMID: 27532257). Functional studies show that this misssense variant, which sits next to a consensus splice site, alters splicing and results in nonsense mediated decay (Carrier L et al., PMID: 9048664; Martson S et al., PMID: 22057632; Helms A et al., PMID: 25031304). This variant is only observed on 5/262,678 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to MYBPC3 function. Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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