rs193922384

Variant names:

• chr11-47332126-T-TGCAGACATAGATGCCCCC
• rs193922384
• NM_000256.3:c.3742_3759dupGGGGGCATCTATGTCTGC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM4 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3742_3759dupGGGGGCATCTATGTCTGC​(p.Cys1253_Arg1254insGlyGlyIleTyrValCys) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,542 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000052957: Experimental evidence suggests that the variant has an effect on protein stability (e.g. Brown_2002, Helms_2014).; SCV000208341: Published functional study demonstrates the absence of mutant protein in septal myectomy and transplant tissue, suggesting this duplication may destabilize the protein and lead to haploinsufficiency (Helms et al., 2014; Helms et al., 2020); SCV000280267: Brown et al (2002) studied the mutant protein in vitro and found that it was less stable than wildtype. They did not observe any differences in binding to myosin. Molecular modeling suggested that the duplicated amino acids were in fact not directly involved in myosin binding, and authors postulated instead may affect some other function of Motif 10, possibly its binding to titin or an alteration in an interaction that may occur with Motif 7 or the adjacent Motif 9. (Oakley et al. 2004).; SCV002049332: Functional studies from multiple groups suggest the variant protein is unstable relative to the wildtype protein (Brown 2002, Glazier 2018, Helms 2014). References: Brown LJ et al. Functional and spectroscopic studies of a familial hypertrophic cardiomyopathy mutation in Motif X of cardiac myosin binding protein-C. Eur Biophys J. 2002 Sep;31(5):400-8. Glazier AA et al. HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C. JCI Insight. 2018 Jun 7;3(11):e99319. Helms AS et al. Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2014 Aug;7(4):434-43.; SCV000546482: Experimental studies have shown that this variant affects MYBPC3 function (PMID:12202917, 25031304).; SCV004836561: "In vitro experimental studies suggest that this in-frame variant affects the expression and structural stability of the MYBPC3 protein." PMID:25031304, 12202917, 29875314; SCV000737356: Functional studies performed in vitro and ex vivo suggest that this duplication results in a mislocalized, unstable protein subject to rapid degradation (Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Glazier AA et al. JCI Insight 2018 Jun;3(11)).; SCV001346706: A functional study has shown that the variant affects protein stability (PMID:25031304).".

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 conservative_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:2
• Conservation: PhyloP100: 1.36
• Publications: 8 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: SCV000052957: Experimental evidence suggests that the variant has an effect on protein stability (e.g. Brown_2002, Helms_2014).; SCV000208341: Published functional study demonstrates the absence of mutant protein in septal myectomy and transplant tissue, suggesting this duplication may destabilize the protein and lead to haploinsufficiency (Helms et al., 2014; Helms et al., 2020); SCV000280267: Brown et al (2002) studied the mutant protein in vitro and found that it was less stable than wildtype. They did not observe any differences in binding to myosin. Molecular modeling suggested that the duplicated amino acids were in fact not directly involved in myosin binding, and authors postulated instead may affect some other function of Motif 10, possibly its binding to titin or an alteration in an interaction that may occur with Motif 7 or the adjacent Motif 9. (Oakley et al. 2004).; SCV002049332: Functional studies from multiple groups suggest the variant protein is unstable relative to the wildtype protein (Brown 2002, Glazier 2018, Helms 2014). References: Brown LJ et al. Functional and spectroscopic studies of a familial hypertrophic cardiomyopathy mutation in Motif X of cardiac myosin binding protein-C. Eur Biophys J. 2002 Sep;31(5):400-8. Glazier AA et al. HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C. JCI Insight. 2018 Jun 7;3(11):e99319. Helms AS et al. Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2014 Aug;7(4):434-43.; SCV000546482: Experimental studies have shown that this variant affects MYBPC3 function (PMID: 12202917, 25031304).; SCV004836561: "In vitro experimental studies suggest that this in-frame variant affects the expression and structural stability of the MYBPC3 protein." PMID:25031304, 12202917, 29875314; SCV000737356: Functional studies performed in vitro and ex vivo suggest that this duplication results in a mislocalized, unstable protein subject to rapid degradation (Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Glazier AA et al. JCI Insight 2018 Jun;3(11)).; SCV001346706: A functional study has shown that the variant affects protein stability (PMID: 25031304).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 23 uncertain in NM_000256.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000256.3.
• PP5: Variant 11-47332126-T-TGCAGACATAGATGCCCCC is Pathogenic according to our data. Variant chr11-47332126-T-TGCAGACATAGATGCCCCC is described in ClinVar as Pathogenic. ClinVar VariationId is 8603.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.3742_3759dupGGGGGCATCTATGTCTGC	p.Cys1253_Arg1254insGlyGlyIleTyrValCys	conservative_inframe_insertion	Exon 33 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.3742_3759dupGGGGGCATCTATGTCTGC	p.Cys1253_Arg1254insGlyGlyIleTyrValCys	conservative_inframe_insertion	Exon 33 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.3742_3759dupGGGGGCATCTATGTCTGC	p.Cys1253_Arg1254insGlyGlyIleTyrValCys	conservative_inframe_insertion	Exon 32 of 34	ENSP00000382193.2	A8MXZ9

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461290 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726930

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41482

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

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: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Hypertrophic cardiomyopathy (3)
2	-	-	Primary familial hypertrophic cardiomyopathy (2)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy 4 (1)
1	-	-	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
-	-	-	Primary dilated cardiomyopathy;C1858725:Left ventricular noncompaction 1;C1861862:Hypertrophic cardiomyopathy 4 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=55/45	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs193922384; hg19: chr11-47353677;