rs397515982

Variant names:

• chr11-47335944-C-T
• rs397515982
• NM_000256.3:c.2670G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2670G>A​(p.Trp890*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000208115: Expression studies using patient heart tissue suggest that the p.(W890X) transcript is subject to nonsense-mediated mRNA decay (Helms et al., 2014);". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.55
• Publications: 12 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AD, AR 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
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000208115: Expression studies using patient heart tissue suggest that the p.(W890X) transcript is subject to nonsense-mediated mRNA decay (Helms et al., 2014)
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47335944-C-T is Pathogenic according to our data. Variant chr11-47335944-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 42650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.2670G>A	p.Trp890*	stop_gained	Exon 26 of 35	NP_000247.2	Q14896-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2670G>A	p.Trp890*	stop_gained	Exon 26 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2670G>A	p.Trp890*	stop_gained	Exon 25 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.*175G>A		non_coding_transcript_exon	Exon 26 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000353 AC: 5 AN: 1414854 Hom.: 0 Cov.: 34 AF XY: 0.00000143 AC XY: 1 AN XY: 700004

African (AFR) AF: 0.00 AC: 0 AN: 31762

American (AMR) AF: 0.00 AC: 0 AN: 38350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24740

East Asian (EAS) AF: 0.00 AC: 0 AN: 37072

South Asian (SAS) AF: 0.00 AC: 0 AN: 79668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4504

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1089112

Other (OTH) AF: 0.00 AC: 0 AN: 58390

GnomAD4 genome Cov.: 30

Alfa AF: 0.00000512 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Hypertrophic cardiomyopathy (4)
1	-	-	Cardiomyopathy (1)
1	-	-	Hypertrophic cardiomyopathy 1 (1)
1	-	-	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
1	-	-	Left ventricular noncompaction 10 (1)
-	-	-	Primary dilated cardiomyopathy;C1858725:Left ventricular noncompaction 1;C1861862:Hypertrophic cardiomyopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.6
Vest4		0.89
GERP RS		5.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs397515982; hg19: chr11-47357495;