rs373746463

Variant names:

• chr11-47333189-C-A
• rs373746463
• NM_000256.3:c.3330+5G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47333189-C-A
• chr11-47333189-C-G
• chr11-47333189-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3330+5G>T variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 11-47333189-C-A is Pathogenic according to our data. Variant chr11-47333189-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3330+5G>T		splice_region_variant, intron_variant	Intron 30 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3330+5G>T		splice_region_variant, intron_variant	Intron 30 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3330+5G>T		splice_region_variant, intron_variant	Intron 29 of 33	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449338 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 719586

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Jun 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 3330+5G>T variant in MYBPC3 has not been previously reported in the literatu re, but has been identified in 1 Caucasian individual and 1 Hispanic individual with HCM out of >3200 probands (>2150 Caucasian and >110 Hispanic) tested by our laboratory. This variant occurs in the 5' splice region. Computational tools su ggest an impact to splicing, though this information is not predictive enough to determine pathogenicity. Another variant at the same position (3330+5G>C) has s hown segregation with disease and causes skipping of exon 30, resulting in a pre mature termination codon that is predicted to lead to a truncated or absent prot ein (Watkins 1995). This variant likely has a similar effect on splicing, but ad ditional studies are needed to establish this with confidence. In summary, addit ional evidence such as with disease and functional effects are required to fully establish the pathogenicity of this variant. -

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 30 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42707). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28679633). This variant disrupts the c.3330+5G nucleotide in the MYBPC3 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 7493025, 25132132, 28679633). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 17, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 25611685, 36264615, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28679633, 7493025, 25132132, 36264615, 37652022, 34461741, 25611685, 23782526, 24704860, 25351510, 28138913) -

Cardiovascular phenotype Pathogenic:1

Sep 21, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3330+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 30 in the MYBPC3 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6194 samples (12388 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, and is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. In addition, alterations at the same position (c.3330+5G>C and c.3330+5G>A) have been reported in association with hypertrophic cardiomyopathy (HCM) (Watkins et al. Nat. Genet.1995 Dec;11(4):434-7; Wang J et al. Eur J Heart Fail. 2014;16(9):950-7). The c.3330+5G>C, alteration segregated with disease in two families, and was reported to result in abnormal splicing leading to skipping of exon 30 and predicted premature protein truncation (Watkins et al. Nat. Genet.1995 Dec;11(4):434-7). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 39

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

Publications

LitVar

Other links and lift over

dbSNP: rs373746463; hg19: chr11-47354740;