rs397516044

Variant names:

• chr11-47331882-C-T
• rs397516044
• NM_000256.3:c.3815-1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3815-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.20

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.3, offset of 8, new splice context is: cctcttctgcaatgcctcAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47331882-C-T is Pathogenic according to our data. Variant chr11-47331882-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47331882-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3815-1G>A		splice_acceptor_variant, intron_variant	Intron 33 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3815-1G>A		splice_acceptor_variant, intron_variant	Intron 33 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3815-1G>A		splice_acceptor_variant, intron_variant	Intron 32 of 33	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000412 AC: 1 AN: 242650 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131818

Gnomad AFR exome AF: 0.0000685

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458124 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724984

Gnomad4 AFR exome AF: 0.0000898

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.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 33 of the MYBPC3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs397516044, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 33673806, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 42746). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in at least fourteen individuals affected with hypertrophic cardiomyopathy including an affected family member (PMID: 25611685, 27532257, 33495596, 33495597, 33663232, 33673806; communication with external laboratories: ClinVar SCV000739990.4, SCV000208208.11). This variant has been identified in 1/242650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 30, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 3815-1G>A variant has not been previously reported or been identified by our laboratory. This variant is predicted to cause abnormal splicing because the nu cleotide substitution occurs in the highly conserved splice consensus sequence. Pathogenic splice variants in MYBPC3 are common in patients with HCM, which sup ports a disease causing role. -

Primary familial hypertrophic cardiomyopathy Pathogenic:3

Dec 07, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.3815-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant is located in intron 33, and the potentially skipped penultimate exon (exon 34) only encodes the last 3 amino acids of the protein, thus the protein level effect of this variant is unclear. The variant allele was found at a frequency of 4.1e-06 in 242650 control chromosomes (gnomAD). c.3815-1G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Alfares_2015, Walsh_2017, Tadros_2021, Harper_2021, Hathaway_2021, Schafer_2021, McGurk_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 42746). The following publications have been ascertained in the context of this evaluation (PMID: 25611685, 27532257, 33495596, 33495597, 33673806, 33663232, 37652022). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Dec 23, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Oct 02, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple patients with cardiomyopathy referred for genetic testing at GeneDx and in the published literature (PMID: 25611685, 27532257, 33673806, 33663232, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant with an unclear effect on protein function; This variant is associated with the following publications: (PMID: 25611685, 27532257, 33673806, 33663232, 37652022) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiomyopathy Pathogenic:1

Jun 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in at least fourteen individuals affected with hypertrophic cardiomyopathy including an affected family member (PMID: 25611685, 27532257, 33495596, 33495597, 33663232, 33673806; communication with external laboratories: ClinVar SCV000739990.4, SCV000208208.11). This variant has been identified in 1/242650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Sep 02, 2022

Clinical Genomics Laboratory, Stanford Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3815-1G>A variant in the MYBPC3 gene has been previously reported in 3 unrelated individuals with HCM (Alfares et al., 2015; Walsh et al., 2017; Hathaway et al., 2021). This variant has also been identified in 1/14604 African/African American chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 42746). This variant alters the canonical acceptor splice site in intron 32, which is predicted to result in abnormal gene splicing. Heterozygous loss of function is an established mechanism of disease for the MYBPC3 gene.These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.38151G>A variant as likely pathogenic for autosomal dominant hypertrophic cardiomyopathy based on the information above. [ACMG evidence codes used: PVS1_Strong; PS4_Supporting; PM2]_x000D_ -

Cardiovascular phenotype Pathogenic:1

Dec 01, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3815-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 34 of the MYBPC3 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This alteration occurs at the 3' terminus of the MYBPC3 gene, is not expected to trigger nonsense-mediated mRNAdecay, and results in a frameshift that is predicted to impact only the last 3 amino acids of the native protein, although it is also expected to elongate the translated protein. The exact functional effect of this alteration is unknown. This variant has been identified in patients with hypertrophic cardiomyopathy (HCM) (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. 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_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Benign	0.64	D
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -9
DS_AL_spliceai		0.89		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516044; hg19: chr11-47353433;