rs730880554

Variant names:

• chr11-47341206-T-A
• rs730880554
• NM_000256.3:c.1829A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000256.3(MYBPC3):​c.1829A>T​(p.Asp610Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D610H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.59
• Publications: 2 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47341207-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42576.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

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.1829A>T	p.Asp610Val	missense	Exon 19 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.1829A>T	p.Asp610Val	missense	Exon 19 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.1829A>T	p.Asp610Val	missense	Exon 18 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.1829A>T		non_coding_transcript_exon	Exon 19 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000449 AC: 1 AN: 222632 AF XY: 0.00000830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000316

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000138 AC: 2 AN: 1447062 Hom.: 0 Cov.: 36 AF XY: 0.00000139 AC XY: 1 AN XY: 718378

African (AFR) AF: 0.00 AC: 0 AN: 33178

American (AMR) AF: 0.0000235 AC: 1 AN: 42632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 38904

South Asian (SAS) AF: 0.00 AC: 0 AN: 83338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105196

Other (OTH) AF: 0.00 AC: 0 AN: 59862

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hypertrophic cardiomyopathy (2)
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.97
MVP		0.95
MPC		0.99
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.91
gMVP		0.98
Mutation Taster		=31/69	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: rs730880554; hg19: chr11-47362757;