rs727503212

Variant names:

• chr11-47347668-TC-T
• rs727503212
• NM_000256.3:c.833delG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.833delG​(p.Gly278GlufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000508 in 1,573,808 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay. The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 3.13
• Publications: 5 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

Specifications for MYBPC3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-47347668-TC-T is Pathogenic according to our data. Variant chr11-47347668-TC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 164140.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.833delG	p.Gly278GlufsTer22	frameshift	Exon 8 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.833delG	p.Gly278GlufsTer22	frameshift	Exon 8 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.833delG	p.Gly278GlufsTer22	frameshift	Exon 8 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.833delG		non_coding_transcript_exon	Exon 8 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151924 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000107 AC: 2 AN: 186304 AF XY: 0.0000100

Gnomad AFR exome AF: 0.0000959

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1421884 Hom.: 0 Cov.: 33 AF XY: 0.00000284 AC XY: 2 AN XY: 703588

African (AFR) AF: 0.0000306 AC: 1 AN: 32692

American (AMR) AF: 0.00 AC: 0 AN: 38656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25302

East Asian (EAS) AF: 0.00 AC: 0 AN: 37722

South Asian (SAS) AF: 0.00 AC: 0 AN: 80978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5314

European-Non Finnish (NFE) AF: 0.00000366 AC: 4 AN: 1092108

Other (OTH) AF: 0.00 AC: 0 AN: 58894

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151924 Hom.: 1 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41320

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Hypertrophic cardiomyopathy (6)
4	-	-	not provided (4)
3	-	-	Hypertrophic cardiomyopathy 4 (3)
2	-	-	Cardiomyopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Left ventricular noncompaction 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
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: rs727503212; hg19: chr11-47369219;