11-47350013-C-T

Variant names:

• chr11-47350013-C-T
• rs730880620
• NM_000256.3:c.505+1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000256.3(MYBPC3):​c.505+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.05
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025882352 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of 6, new splice context is: agtGTgagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47350013-C-T is Pathogenic according to our data. Variant chr11-47350013-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181041.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.505+1G>A		splice_donor intron	N/A	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.505+1G>A		splice_donor intron	N/A	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.505+1G>A		splice_donor intron	N/A	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.505+1G>A		splice_donor intron	N/A	ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408074 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 695456

African (AFR) AF: 0.00 AC: 0 AN: 31954

American (AMR) AF: 0.00 AC: 0 AN: 36806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25270

East Asian (EAS) AF: 0.00 AC: 0 AN: 36288

South Asian (SAS) AF: 0.00 AC: 0 AN: 79776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084254

Other (OTH) AF: 0.00 AC: 0 AN: 58352

GnomAD4 genome Cov.: 33

Alfa AF: 0.000136 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

May 13, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Although the c.505+1 G>A mutation has not been reported as a disease - causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 4 of the MYBPC3 gene and is predicted to cause abnormal gene splicing. The mutation is expected to lead to either an abnormal message that is subject to nonsense - mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the MYBPC3 gene have been reported in association with HCM. The variant is found in HCM panel(s).

Hypertrophic cardiomyopathy Pathogenic:1

Aug 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 181041). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Cardiovascular phenotype Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.505+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the MYBPC3 gene. This alteration has been detected in hypertrophic cardiomyopathy (HCM) cohorts and in a sudden unexplained death cohort; however, clinical details were limited (Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405; Guo L et al. JAMA Cardiol. 2021 Sep;6(9):1013-1022; Sepp R et al. Diagnostics (Basel). 2022 May;12(5)). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.0
GERP RS		3.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: -5
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs730880620; hg19: chr11-47371564;