NM_000256.3:c.1790G>A

Variant names:

• chr11-47341991-C-T
• rs727503195
• NM_000256.3:c.1790G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1790G>A​(p.Arg597Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000154 in 1,557,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000318810: "In one study, an in vitro minigene splicing assay has suggested this variant results in out-of-frame skipping of exon 18 which results in the introduction of a premature truncation codon (Millat G et al. DNA Cell Biol. 2015;34:489-96), and a second minigene assay has also suggested aberrant splicing impact (Ito K. Proc. Natl. Acad. Sci. U.S.A.. 2017 Jul;114(29):7689-7694)."; SCV000198884: An in vitro functional study showed that cells harboring this variant produced a shorter mRNA product than wild type cells, consistent with skipping of exon 18 (Millat 2015).; SCV000749869: Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:25849606, 28679633).; SCV004828387: Studies using in vitro hybrid minigene assays suggested aberrant splicing impact from the c.1790G>A variant and an altered mRNA splicing leading to a premature termination codon (PMID:28679633).; SCV000208050: Published functional studies demonstrate a damaging effect as this variant results in abnormal splicing and skipping of exon 18 in HeLa cells (PMID:25849606); SCV006061203: Functional mini-gene assays have shown that this variant is expected to cause an out-of-frame skipping of exon 18 (PMID:25849606, 28679633).; SCV001984857: "In-vitro studies in mammalian cells using a mini gene assays have shown that this missense change results in aberrant splicing." PMID:25849606, 28679633; SCV005417288: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV007096757: A minigene assay has shown abnormal splicing and skipping of exon 18 in HeLa cells (PMID:25849606); SCV006333733: Experimental studies have shown that this variant affects the function of the gene (Millat G, et al., 2015).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R597W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.53
• Publications: 17 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000318810: "In one study, an in vitro minigene splicing assay has suggested this variant results in out-of-frame skipping of exon 18 which results in the introduction of a premature truncation codon (Millat G et al. DNA Cell Biol. 2015;34:489-96), and a second minigene assay has also suggested aberrant splicing impact (Ito K. Proc. Natl. Acad. Sci. U.S.A.. 2017 Jul;114(29):7689-7694)."; SCV000198884: An in vitro functional study showed that cells harboring this variant produced a shorter mRNA product than wild type cells, consistent with skipping of exon 18 (Millat 2015).; SCV000749869: Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25849606, 28679633).; SCV004828387: Studies using in vitro hybrid minigene assays suggested aberrant splicing impact from the c.1790G>A variant and an altered mRNA splicing leading to a premature termination codon (PMID: 28679633).; SCV000208050: Published functional studies demonstrate a damaging effect as this variant results in abnormal splicing and skipping of exon 18 in HeLa cells (PMID: 25849606); SCV006061203: Functional mini-gene assays have shown that this variant is expected to cause an out-of-frame skipping of exon 18 (PMID: 25849606, 28679633).; SCV001984857: "In-vitro studies in mammalian cells using a mini gene assays have shown that this missense change results in aberrant splicing." PMID:25849606, 28679633; SCV005417288: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV007096757: A minigene assay has shown abnormal splicing and skipping of exon 18 in HeLa cells (PMID: 25849606); SCV006333733: Experimental studies have shown that this variant affects the function of the gene (Millat G, et al., 2015).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 11-47341991-C-T is Pathogenic according to our data. Variant chr11-47341991-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 164098.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.1790G>A	p.Arg597Gln	missense splice_region	Exon 18 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.1790G>A	p.Arg597Gln	missense splice_region	Exon 18 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.1790G>A	p.Arg597Gln	missense splice_region	Exon 17 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.1790G>A		splice_region non_coding_transcript_exon	Exon 18 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000300 AC: 5 AN: 166884 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000119

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: 0.0000121 AC: 17 AN: 1405486 Hom.: 0 Cov.: 32 AF XY: 0.0000115 AC XY: 8 AN XY: 693736

African (AFR) AF: 0.00 AC: 0 AN: 31978

American (AMR) AF: 0.0000833 AC: 3 AN: 36004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25252

East Asian (EAS) AF: 0.0000552 AC: 2 AN: 36210

South Asian (SAS) AF: 0.000100 AC: 8 AN: 79814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1082004

Other (OTH) AF: 0.00 AC: 0 AN: 58430

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.000393 AC: 6 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00000465 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00000856 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Hypertrophic cardiomyopathy (5)
3	-	-	Hypertrophic cardiomyopathy 4 (3)
3	-	-	not provided (3)
2	-	-	Cardiomyopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Left ventricular noncompaction 10 (1)
1	-	-	MYBPC3-related cardiomyopathies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0060	D
Vest4		0.95
MVP		0.87
MPC		0.88
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.51
gMVP		0.78
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 17
DS_DL_spliceai		0.32		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503195; hg19: chr11-47363542;