NM_000256.3:c.270C>G

Variant names:

• chr11-47351261-G-C
• rs367990952
• NM_000256.3:c.270C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_000256.3(MYBPC3):​c.270C>G​(p.Phe90Leu) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F90F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.35
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75
• PP5: Variant 11-47351261-G-C is Pathogenic according to our data. Variant chr11-47351261-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 191021.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.270C>G	p.Phe90Leu	missense	Exon 2 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.270C>G	p.Phe90Leu	missense	Exon 2 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.270C>G	p.Phe90Leu	missense	Exon 2 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.270C>G		non_coding_transcript_exon	Exon 2 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.31
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.49		Gain of ubiquitination at K93 (P = 0.0599)
MVP		0.62
MPC		0.90
ClinPred		0.94	D
GERP RS		1.8
Varity_R		0.82
gMVP		0.65
Mutation Taster		=41/59	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: rs367990952; hg19: chr11-47372812;