11-47337450-G-T

Variant names:

• chr11-47337450-G-T
• rs730880569
• NM_000256.3:c.2543C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000256.3(MYBPC3):​c.2543C>A​(p.Ala848Glu) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A848V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 9.60
• Publications: 7 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 40 uncertain in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 11-47337450-G-T is Pathogenic according to our data. Variant chr11-47337450-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220872.

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.2543C>A	p.Ala848Glu	missense	Exon 25 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2543C>A	p.Ala848Glu	missense	Exon 25 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.2543C>A	p.Ala848Glu	missense	Exon 24 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.*48C>A		non_coding_transcript_exon	Exon 25 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
1	-	-	Hypertrophic cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		9.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.99
MVP		0.95
MPC		0.90
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.97
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730880569; hg19: chr11-47359001;