rs397516029

chr11-47332568-TG-Tchr11-47332568-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3624del(p.Lys1209SerfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,605,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -0.203

Variant links:

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:

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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 11-47332568-TG-T is Pathogenic according to our data. Variant chr11-47332568-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 42727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332568-TG-T is described in Lovd as [Pathogenic]. Variant chr11-47332568-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3624del	p.Lys1209SerfsTer28	frameshift_variant	32/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3624del	p.Lys1209SerfsTer28	frameshift_variant	32/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3624del	p.Lys1209SerfsTer28	frameshift_variant	31/34	5		A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246920

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133944

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453406

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721266

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 11, 2016	p.Lys1209Serfs28 (c.3624delC) in exon 32 of the MYBPC3 gene (NM_000256.3) We have seen this variant in 2 unrelated people with HCM. Testing was done by Invitae in both cases. Loss of function caused by frameshift variants are a well established mechanism of disease in this gene. In addition, there is strong case data for this variant and it is sufficiently rare in population datasets. Therefore, we consider this variant very likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Please note that this variant may also be called Pro1208ProfsX29. The variant has been seen in at least 10 unrelated cases of HCM (not including our patients' families). This is strong case data, but there is no reported segregation data. Li et al., 2009 reported this variant in a 59 year-old Chinese woman with HCM. Zou et al., 2013 reported this variant in 3 unrelated Chinese people with HCM. Liu et al., 2013 reported this variant in 2 unrelated Chinese people with HCM. Liu et al., 2015 reported the variant in 2 unrelated people with HCM. The variant is listed in ClinVar, classifed as Pathogenic by LMM, GeneDx, and Invitae (as of 10/11/2016). LMM reports that they have seen the variant in two families with HCM, one Asian and one Caucasian. Per the Invitae report, "This sequence change deletes 1 nucleotide from exon 32 of the MYBPC3 mRNA (c.3624delC), causing a frameshift at codon 1209. This creates a premature translational stop signal (p.Lys1209Serfs28) and is expected to result in an absent or disrupted protein product." The variant was reported online in 2 of 140,093 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on 126,216 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent (as of 10/2016). Specifically, the variant was observed in 1 of 9,432 individuals of East Asian descent (0.005% MAF) and 1 of 62,724 people of non-Finnish European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2022	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 20128375, 23283745, 28498465, 28614222, 26914223, 26090888, 27532257, 28241245, 28790153, 28408708, 28615295, 27112610, 23711808, 23549607, 29497013, 33673806) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 06, 2018	- -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 16, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42727). This variant is also known as p.Pro1208fs. This premature translational stop signal has been observed in individual(s) with MYBPC3-related conditions (PMID: 20128375, 23283745, 23711808, 26090888). This variant is present in population databases (rs397516030, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Lys1209Serfs*28) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2020	The p.Lys1209SerfsX28 variant in MYBPC3 (also reported as p.Pro1208fs in the literature) has been identified in at least 10 unrelated individuals with hypertrophic cardiomyopathy (HCM; including an individual who also carried a disease causing variant in another HCM associated gene) and segregated with disease in at least 2 affected relatives from 2 families (Li 2009, Zou 2013, Liu 2013, Liu 2015, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID 42727) and has been identified in 0.005% (1/19456) of East Asian chromosomes and 1/127178 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 1209 and leads to a premature termination codon 28 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PS4_Strong. -
Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 10, 2019	The MYBPC Lys1209Serfs28 has been reported previously in several HCM patients and is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this MYBPC3 Lys1209Serfs28 variant in two HCM probands, one of our probands has a family history of HCM, however genetic testing was not possible. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been reported in more than 6 unrelated HCM probands (PS4_moderate) and is rare in the general population (PM2), therefore we classify MYBPC3 Lys1209Serfs*28 as a "pathogenic" variant. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 31, 2022

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 18, 2021

Variant summary: MYBPC3 c.3624delC (p.Lys1209SerfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 246920 control chromosomes (gnomAD). c.3624delC has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Liu_2015, and Murphy_2016, Ross_2017, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

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Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over