NM_000256.3:c.655G>C

Variant names:

• chr11-47348541-C-G
• rs397516068
• NM_000256.3:c.655G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM5 PP5_Very_Strong BP4

The NM_000256.3(MYBPC3):​c.655G>C​(p.Val219Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,458,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000208238: RNA studies demonstrate a damaging effect as a majority of reads result in no splicing occurring (PMID:34461741);; SCV000059311: "In vitro studies showed that this variant results in skipping of exon 6 (Crehalet 2012), which is predicted to cause a frameshift and a premature termination codon, leading to a truncated or absent protein." PMID:29655203; SCV000284250: Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (Crehalet 2012; http://dx.doi.org/10.4081/cardiogenetics.2012.e6).; SCV004814328: Functional studies have showed that the c.655G>C change causes skipping of exon 6, which is predicted to result in a truncated protein or absence of the protein (Crehalet et al., 2012).; SCV000740158: "In an in vitro minigene assay, this alteration caused complete skipping of exon 6, which is expected to lead to a frameshift and introduce an alternate stop (p.V219Rfs*42)" (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694).; SCV004358772: In-vitro functional mini-gene assays have shown that this variant is expected to cause skipping of exon 6; this 118 base pair deletion is expected to create a frameshift and premature translation stop signal, expected to result in an absent or non-functional protein product (PMID:28679633; DOI:10.4081/cardiogenetics.2012.e6).; SCV001754766: Functional studies have showed that the c.655G>C change causes skipping of exon 6, which is predicted to result in a truncated protein or absence of the protein (Crehalet et al., 2012).; SCV005398720: "This variant has been functionally proven to cause skipping of exon 6, which is an out-of-frame exon. The protein consequence is unknown; however, a frameshift and nonsense-mediated decay (NMD) is expected (ClinVar, Crehalet, H. et al. (2012))"; p.(Val219Phe) has been reported as pathogenic (ClinVar), and has also been functionally proven to result in exon 6 skipping (Crehalet, H. et al. (2012)).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V219F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 0.9383
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 2.08
• Publications: 24 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000208238: RNA studies demonstrate a damaging effect as a majority of reads result in no splicing occurring (PMID: 34461741);; SCV000059311: "In vitro studies showed that this variant results in skipping of exon 6 (Crehalet 2012), which is predicted to cause a frameshift and a premature termination codon, leading to a truncated or absent protein." PMID:29655203; SCV000284250: Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (Crehalet 2012; http://dx.doi.org/10.4081/cardiogenetics.2012.e6).; SCV004814328: Functional studies have showed that the c.655G>C change causes skipping of exon 6, which is predicted to result in a truncated protein or absence of the protein (Crehalet et al., 2012).; SCV000740158: "In an in vitro minigene assay, this alteration caused complete skipping of exon 6, which is expected to lead to a frameshift and introduce an alternate stop (p.V219Rfs*42)" (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694).; SCV004358772: In-vitro functional mini-gene assays have shown that this variant is expected to cause skipping of exon 6; this 118 base pair deletion is expected to create a frameshift and premature translation stop signal, expected to result in an absent or non-functional protein product (PMID: 28679633; DOI:10.4081/cardiogenetics.2012.e6).; SCV001754766: Functional studies have showed that the c.655G>C change causes skipping of exon 6, which is predicted to result in a truncated protein or absence of the protein (Crehalet et al., 2012).; SCV005398720: "This variant has been functionally proven to cause skipping of exon 6, which is an out-of-frame exon. The protein consequence is unknown; however, a frameshift and nonsense-mediated decay (NMD) is expected (ClinVar, Crehalet, H. et al. (2012))"; p.(Val219Phe) has been reported as pathogenic (ClinVar), and has also been functionally proven to result in exon 6 skipping (Crehalet, H. et al. (2012)).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47348541-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 11-47348541-C-G is Pathogenic according to our data. Variant chr11-47348541-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.42361706). . Strength limited to SUPPORTING due to the PP5.

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.655G>C	p.Val219Leu	missense splice_region	Exon 6 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.655G>C	p.Val219Leu	missense splice_region	Exon 6 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.655G>C	p.Val219Leu	missense splice_region	Exon 6 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.655G>C		splice_region non_coding_transcript_exon	Exon 6 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1458236 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 725106

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1109916

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000219 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hypertrophic cardiomyopathy 4 (4)
4	-	-	not provided (4)
3	-	-	Hypertrophic cardiomyopathy (3)
2	-	-	Cardiomyopathy (2)
1	-	-	Asymmetric septal hypertrophy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
1	-	-	Left ventricular noncompaction 10 (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.055
Eigen_PC	Benign	0.0046
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.012	D
Polyphen		0.88	P
Vest4		0.49
MVP		0.85
MPC		0.46
ClinPred		0.75	D
GERP RS		2.9
Varity_R		0.39
gMVP		0.56
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.65
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: rs397516068; hg19: chr11-47370092;