rs397515963

chr11-47337729-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000256.3(MYBPC3):c.2373_2374insG(p.Trp792ValfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,563,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:31 O:1
• Conservation: PhyloP100: 0.107

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-47337729-A-AC is Pathogenic according to our data. Variant chr11-47337729-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 42619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2373_2374insG	p.Trp792ValfsTer41	frameshift_variant	24/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2373_2374insG	p.Trp792ValfsTer41	frameshift_variant	24/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2373_2374insG	p.Trp792ValfsTer41	frameshift_variant	23/34	5		A2
MYBPC3	ENST00000544791.1	c.2373_2374insG	p.Trp792ValfsTer16	frameshift_variant, NMD_transcript_variant	24/27	5

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151760 Hom.: 0 Cov.: 31

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000174 AC: 3 AN: 172018 Hom.: 0 AF XY: 0.0000109 AC XY: 1 AN XY: 91808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000428

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000276 AC: 39 AN: 1412080 Hom.: 0 Cov.: 33 AF XY: 0.0000301 AC XY: 21 AN XY: 697906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000350

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151760 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74092

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2022	The MYBPC3 c.2373dup; p.Trp792ValfsTer41 variant (rs397515963), also known as 2373insG or InsG791, is reported in the literature as a pathogenic founder variant associated with hypertrophic cardiomyopathy (HCM), particularly in individuals of Dutch ancestry (Alders 2003, Moolman 2000, Nannenberg 2011, Niimura 1998). This variant has been reported to segregate with disease with incomplete penetrance in multiple large families affected with HCM (Alders 2003, Moolman 2000, Nannenberg 2011, Niimura 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 42619) and is found in the general population with a low overall allele frequency of 0.002% (3/172018 alleles) in the Genome Aggregation Database. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Computational analyses (Alamut v.2.11) also predict that this variant may impact splicing by creating a novel cryptic donor splice site, and functional analyses of the variant protein show use of the cryptic splice site, leading to a frameshift and haploinsufficiency (Moolman 2000, van Dijk 2009). Based on available information, the c.2373dup variant is considered to be pathogenic. References: Alders M et al. The 2373insG mutation in the MYBPC3 gene is a founder mutation, which accounts for nearly one-fourth of the HCM cases in the Netherlands. Eur Heart J. 2003 Oct;24(20):1848-53. PMID: 14563344 Moolman JA et al. A newly created splice donor site in exon 25 of the MyBP-C gene is responsible for inherited hypertrophic cardiomyopathy with incomplete disease penetrance. Circulation. 2000 Mar 28;101(12):1396-402. PMID: 10736283. Nannenberg EA et al. Mortality risk of untreated myosin-binding protein C-related hypertrophic cardiomyopathy: insight into the natural history. J Am Coll Cardiol. 2011 Nov 29;58(23):2406-14. PMID: 22115648 Niimura H et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998 Apr 30;338(18):1248-57. PMID: 9562578. van Dijk SJ et al. Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction. Circulation. 2009 Mar 24;119(11):1473-83. PMID: 19273718 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2022	Observed in individuals with severe infantile-onset cardiomyopathy who were either homozygous for this variant or compound heterozygous for this variant and a second pathogenic variant in the MYBPC3 gene (Lekanne Deprez et al., 2006; Haberer et al., 2014; Wessels et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate c.2373dupG causes haploinsufficiency, deranged phosphorylation of contractile proteins, reduced maximal force-generating capacity of cardiomyocytes, and enhanced Ca2+ sensitivity (van Dijk et al., 2009); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30731207, 29759671, 23674513, 22569109, 20705073, 27532257, 28615295, 28005231, 20505798, 24111713, 19356534, 19666645, 25262865, 23396983, 23074333, 26489474, 21257752, 22115648, 9562578, 27476098, 22173300, 24510615, 16679492, 25335496, 28794111, 22574137, 29540445, 28971120, 29169752, 30025578, 29237689, 28790153, 19574547, 29212898, 26914223, 29447731, 29121657, 27108529, 30775854, 30742251, 31006259, 30550750, 31737537, 32880476, 14563344, 32686758, 32746448, 19273718, 31513939, 33849460, 33662488, 33673806, 30847666, 34135346, 33726816, 33087929) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 25, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp792ValfsX41 (c.2373dupG) in MYBPC3. Based on the data reviewed below we consider this variant very likely disease-causing. This variant is in exon 24 of the MYBPC3 gene. The c.2373dupG variant causes a shift in the reading frame beginning with Tryptophan residue 792 changing to a Valine and creating a premature stop codon at position 41 of the new reading frame. It is expected to results in an abnormal, truncated protein or in absence of protein due to mRNA decay. Nonsense and splicing variants are frequently seen in MYBPC3 in association with cardiomyopathy. To the best of our knowledge no experimental studies have demonstrated impact on splicing or the final protein product. Moolman et al (2000) were not able to identify a truncated protein product using immunohistochemistry. In total this variant has been observed in at least ~14 unrelated individuals with HCM, though three of those cases were shown to share a common founder. We have seen it in 6 families with HCM, including this patient’s family (as of October 29, 2014). Nimura et al (1998) reported this variant in 3 families with HCM. In those families 115 individuals were genotype positive for the variant; of these 45 individuals were phenotype positive for HCM. There were 10 reported disease related deaths among this group. Haplotype analysis indicated that this was a founder mutation in these 3 families. Moolman et al (2000) also described a family with HCM with this variant. A family of 49 individuals was analyzed in this publication, out of these 27 were found to be genotype positive for the variant – 10 individuals fulfilled the diagnostic criteria for HCM, 5 individuals were borderline for the disease, 12 had normal echo/ecgs and no symptoms, 2 individuals required a myectomy and 2 individuals experienced a SCD event. Alders et al (2003) reported that this variant is common in HCM patients in the Netherlands. GeneDx also reports this variant has been seen in multiple unrelated individuals tested for HCM at their laboratory(many of whom likely include our patients). This variant has been reported in multiple additional cases of HCM and (Maron et al 2001; Ortlepp et al 2002; Waldmuller et al 2002; Richard et al 2003; Van Driest et al 2004; Barr et al 2001).Some authors have suggested that this variant is associated with later onset of disease. In the kindred reported by Moolman et al (200), age of onset was late in life (often after than 30 yrs old), and Kaplan Meier survival curve illustrated near normal survival at age 50 (95%). In total the variant has not been seen in 7,200 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 792 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/15/14). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 10/15/13). The variant was not observed in the following laboratory and published control samples: Van Driest et al (2004) did not observe the variant in 200 presumably healthy controls of unknown ancestry. Based on literature review it is unclear if the control populations used in the Niimura and Moolman publications are the same or if they represent 2 distinct groups of normal individuals-each report 100 controls. Review of a Familion/PGX testing report on the variant indicates that they did not find the variant in 400 presumably healthy control individuals (July 2009). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MYBPC3: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 09, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 4 Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Jun 09, 2020	PVS1, PS4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 16, 2022	_x000D_reported as incidental finding according to ACMG Criteria applied: PVS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 31, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PVS1,PS3,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 01, 2023	PVS1, PS4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 28, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Jan 01, 2016	This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the variant has been reported previously in individuals with cardiomyopathy. Functional studies demonstrate that this variant causes abberrant phosphorylation of contractile proteins, reduced maximal force-generating capacity of cardiomyocytes, and enhanced Ca2+ sensitivity (PMID: 19273718 ). -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 25, 2017	- -

Hypertrophic cardiomyopathy Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 05, 2024	This variant inserts 1 nucleotide in exon 24 of the fibronectin type 3 domain C6 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. RNA studies has shown that this variant may create a new splice donor site, which could also result in a frameshift and premature truncation (PMID: 10736283). This variant has been reported in over 300 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 14563344, 19273718, 20505798, 22115648, 22574137, 35653365) and occurs in up to 25% of Dutch individuals affected with hypertrophic cardiomyopathy (PMID: 14563344, 20505798). A study of a large multigenerational family affected with hypertrophic cardiomyopathy has shown that penetrance of this variant is incomplete and age-dependent (PMID: 10736283). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 32880476), and it has also been reported in compound heterozygous or homozygous state in three Dutch neonates with lethal cardiomyopathy (PMID: 25335496). This variant has been identified in 3/172018 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 24, 2020	MYBPC3 Trp792fs has been well described in multiple families and individuals with HCM (see literature). It is one of three main founder mutations in MYBPC3 in HCM patients in the Netherlands (Alders M, et al., 2003; Christianns I, et al., 2010). This Trp792fs mutation accounts for nearly 25% of all HCM cases in the Netherlands (Alders M, et al., 2003). Familial segregation (where available) shows evidence of co-segregation (Niimura H, et al., 1998; Moolman JA, et al., 2000; Maron BJ, et al., 2001). The variant is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this MYBPC3 Trp792fs mutation in 12 unrelated HCM probands and the variant has been found to segregate with disease in several of our families. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant results in loss of function of MYBPC3 (PVS1), has been identified in well over 15 HCM probands (PS4), segregates strongly with disease (PP1_strong) and is rare in the general population (PM2), therefore we classify MYBPC3 Trp792fs as 'pathogenic'. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Feb 09, 2017	ACMG score pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change creates a premature translational stop signal (p.Trp792Valfs*41) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397515963, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (HCM) or neonatal cardiomyopathy with features of left ventricular non-compaction and septal defects (PMID: 9562578, 10736283, 19273718, 22115648, 22574137, 25335496). It is commonly reported in individuals of Dutch ancestry (PMID: 14563344, 20505798). ClinVar contains an entry for this variant (Variation ID: 42619). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 03, 2022	The p.Trp792ValfsX41 variant in MYBPC3 has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and has shown strong segregation with disease in multiple families (Niimura 1998 PMID: 9562578, Moolman 2000 PMID: 10736283, Maron 2001 PMID: 11499718, Ortlepp 2002 PMID: 11847170, Alders 2003 PMID: 14563344, Walsh 2017 PMID: 27532257, LMM data). This variant a likely Dutch founder variant and is estimated to account for approximately 25% of cases of HCM in the Netherlands (Alders 2003 PMID: 14563344). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42619) and has been identified in 0.004% (3/70142) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability and incomplete or age-dependent penetrance, pathogenic variants may be present at a low frequency in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 792 and leads to a premature termination codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In vitro functional studies support that this variant leads to a loss-of-function (Moolman 2000 PMID: 10736283). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Loeys Lab, Universiteit Antwerpen	Feb 26, 2021	This sequence change results in a frameshift variant in the MYBPC3 gene (p.(Trp792ValFs*41)) resulting in loss-of function and haploinsufficiency, which is a known disease mechanism(PVS1) (PMID: 19273718). This variant is present in population databases (GnomAD 3/166724). This variant has been reported in the literature in several families with HCM and showed co-seggregation with HCM (PP1strong) (PMID:9562578; PMID: 10736283; PMID: 14563344; PMID: 19356534; PMID: 23674513; PMID: 24111713; PMID: 27476098; PMID:25335496).It has been described as a Dutch Founder variant, present in 17-25% of all HCM cases (PS4) (PMID: 20505798, 14563344).Functional studies demonstrated that the variant reduced maximal force-generating capacity of cardiomyocytes(PS3) (PMID: 19273718). We identified this variant in two HCM families. In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1strong; PS4;PS3). -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2023	This variant inserts 1 nucleotide in exon 24 of the fibronectin type 3 domain C6 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. RNA studies have shown that this variant creates a new splice donor site, which could also result in a frameshift and premature truncation (PMID: 10736283). This variant has been reported in over 300 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 14563344, 19273718, 20505798, 22115648, 22574137, 35653365) and occurs in up to 25% of Dutch individuals affected with hypertrophic cardiomyopathy (PMID: 14563344, 20505798). A study of a large multigenerational family affected with hypertrophic cardiomyopathy has shown that penetrance of this variant is incomplete and age-dependent (PMID: 10736283). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 32880476), and it has also been reported in compound heterozygous or homozygous state in three Dutch neonates with lethal cardiomyopathy (PMID: 25335496). This variant has been identified in 3/172018 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 14, 2023	- -

Primary familial hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 27, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2017	Variant summary: The MYBPC3 c.2373dupG (p.Trp792ValfsX41) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A functional study, Van Dijk_2009, supports this variant causing loss-of-function. This variant was found in 3/166724 control chromosomes (gnomAD) at a frequency of 0.000018, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). Multiple publications have cited the variant in affected individuals, predominantly of Dutch origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 14, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2018

The c.2373dupG pathogenic mutation, located in coding exon 24 of the MYBPC3 gene, results from a duplication of G at nucleotide position 2373, causing a translational frameshift with a predicted alternate stop codon (p.W792Vfs*41). This mutation has been identified in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM), reported to co-segregate with disease in several families, and is published as a Dutch founder mutation (Niimura et al. N Engl J Med. 1998;338(18):1248-57 (reported as InsG791); Alders et al. Eur Heart J. 2003;24(20):1848-53; Christiaans et al. Neth Heart J. 2010;18(5):248-54 (reported as 2373_2374insG)). In the homozygous state, this mutation has been reported in a patient with neonatal lethal cardiomyopathy (Wessels MW et al. Eur. J. Hum. Genet., 2015 Jul;23:922-8). In addition, multiple functional studies have reported this mutation to result in loss of function (Moolman et al. Circulation. 2000;101(12):1396-402; van Dijk et al. Circulation. 2009;119(11):1473-83; Marston S et al. J Muscle Res Cell Motil. 2012;33(1):75-80; Wijnker PJ et al. J. Mol. Cell. Cardiol., 2016 Aug;97:82-92 (reported as 2373_2374insG)). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

MYBPC3-related disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 11-17-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515963; hg19: chr11-47359280;