dbSNP rs397515926: MYBPC3:p.Lys600AsnfsTer2 (chr11-47341234-GT-G) – ACMG Classification: Pathogenic (18 pts)

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-47341234-GT-G is Pathogenic according to our data. Variant chr11-47341234-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 42568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47341234-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.1800delA	p.Lys600AsnfsTer2	frameshift_variant	Exon 19 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.1800delA	p.Lys600AsnfsTer2	frameshift_variant	Exon 19 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.1800delA	p.Lys600AsnfsTer2	frameshift_variant	Exon 18 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.1800delA		non_coding_transcript_exon_variant	Exon 19 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000491

AC:

AN:

203524

Hom.:

AF XY:

0.00

AC XY:

AN XY:

109684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000339

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1435652

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000245

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 07, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Lys600AsnfsX2 (p.K600NfsX2, p.K600Nfs, p.Lys600Nfs c.1800delA) in exon 19 of the MYBPC3 gene (NM_000256.3). Given that frameshift variants in this gene are a common cause of HCM and that there is strong case and segregation data, we consider this variant very likely disease causing. The variant has been seen in at least 11 unrelated cases of (not including this patient's family). Richard et al (2003) reported the variant in one of 197 unrelated HCM patients from their French cohort. Most were of European ancestry. They analyzed 9 sarcomere genes. Note they refer to the variant as del A 12413 (I found multiple sources that map this as the same variant as p.Lys600AsnfsX2). No segregation data was provided. Brito et al (2012) observed the variant in one of 77 HCM patients from their Portuguese cohort that underwent analysis of 5 sarcomere genes. They note that segregation analysis was performed but don't give specific data for this variant. I found a Spanish publication that appears to be about preimplantation genetic diagnosis for this variant (Vendrell et al 2009). Rodriguez-Garcia et al (2010) reported the variant in two brothers with HCM from their Spanish cohort of 130 HCM patients. They only analyzed MYBPC3 in this study. The same group included a patient with this variant in a paper on conduction system disease in HCM (Barriales-Villa et al 2010). Unfortunately insufficient case details are available to determine if it is the same patient described in the other report. This group also published a very interesting family with a father and daughter with HCM and this variant and mother and son with hypertrabeculation (Ortiz et al 2009). The son did not carry the variant and presumably inherited hypertrabeculation from his mother. Interestingly, the authors note that they have a total of 8 families with HCM and this variant with 21 carriers and 90% penetrance by 30 years of age (also reported in a poster, Ortiz et al, http://spo.escardio.org/eslides/view.aspx?eevtid=33&fp=3253). There were three different families with three affected members with the variant, including one set of three first cousins. It is in ClinVar with a submission from LMM, classifying it as pathogenic, but not including internal case data (SCV000059083). Michels et al (2011) observed the variant in 1 of 327 unrelated Dutch HCM patients. No individual ancestry or phenotype data was reported. They only analyzed MYBPC3. This is a frame-shifting variant that creates a premature stop codon 2 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. Many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012).. In total the variant has not been seen in ~6800 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 15th, 2014). Note that this dataset does not match the patient's ancestry (Hispanic). The variant is listed in dbSNP (rs397515926), however the only submission is from LMMM. The variant was not observed in the following published control samples: 100 healthy adults (Richard et al 2003), 200 controls (Rodriguez-Garcia et al 2010). -

Feb 13, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple unrelated patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 12707239, 22857948, 27532257); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22857948, 27153395, 27532257, 31589614, 37652022, 20433692, 20738943, 12707239, 37317833) -

Hypertrophic cardiomyopathy

Pathogenic:3

Apr 10, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 19 of the Ig-like domain C4 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 20433692, 20738943, 22857948, 27532257, 33495597). This variant has been identified in 1/203524 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Dec 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys600fs variant in MYBPC3 has been identified by our laboratory in 2 adul ts with HCM. This frameshift variant is predicted to alter the protein?s amino a cid sequence beginning at position 600 and lead to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a trunca ted or absent protein. Heterozygous loss of function of the MYBPC3 gene is an es tablished disease mechanism in HCM patients. In summary, this variant meets crit eria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon c onsistency with the established disease causing mechanism. -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys600Asnfs*2) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397515926, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20433692, 22857948, 27532257). ClinVar contains an entry for this variant (Variation ID: 42568). For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy 4

Pathogenic:2

Aug 14, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited c.1800del (p.Lys600AsnfsTer2) variant identified in the MYBPC3 gene is the deletion of a single nucleotide resulting in a frameshift at amino acid 600/1275 (exon 19/35) and is predicted to lead to the premature termination of the protein 2 amino acids downstream. This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. Loss-of-function variants in MYBPC3 are known to be pathogenic [PMID: 19574547]. The c.1800del (p.Lys600AsnfsTer2) variant is reported in ClinVar as Pathogenic by multiple submitters (VarID: 42568) and has been reported in several individuals affected with hypertrophic cardiomyopathy in the literature [PMID: 12707239, 20433692, 22857948, 27532257, 20738943]. Given this variant is predicted to lead to the premature termination of the protein, its presence in affected individuals in the literature, and absence in population databases, the c.1800del (p.Lys600AsnfsTer2) variant identified in the MYBPC3 gene is reported as Pathogenic. -

Cardiomyopathy

Pathogenic:1

Mar 15, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Jun 07, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1800delA pathogenic mutation, located in coding exon 19 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 1800, causing a translational frameshift with a predicted alternate stop codon (p.K600Nfs*2). This alteration (also known as g.12413delA) was reported in two individuals with hypertrophic cardiomyopathy (Richard P et al. Circulation 2003; 107(17):2227-32; Brito D et al. Rev Port Cardiol 2012; 31(9):577-87). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

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Splicing

Name

Calibrated prediction

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SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs397515926

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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