Submissions for variant NM_000256.3(MYBPC3):c.177_187del (p.Glu60fs)

dbSNP: rs397515925

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000461041	SCV000059080	pathogenic	Hypertrophic cardiomyopathy	2019-02-01	criteria provided, single submitter	clinical testing	The p.Glu60AlafsX49 variant in MYBPC3 has been reported in 9 individuals with HCM (7 individuals: Zimmerman 2010, Alfares 2015, Walsh 2016; 1 individual: Burns 2016; 1 individual: Murphy 2017) and segregated with disease in 1 affected (LMM data). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 42565). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 60 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate.
GeneDx	RCV000158384	SCV000208319	pathogenic	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation and 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: 20474083, 25228707, 25611685, 26914223, 27532257, 28790153, 23690394, 24510615, 21943931, 21415409, 25543971)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461041	SCV000546433	pathogenic	Hypertrophic cardiomyopathy	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu60Alafs*49) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 20474083). ClinVar contains an entry for this variant (Variation ID: 42565). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228152	SCV000696319	pathogenic	Primary familial hypertrophic cardiomyopathy	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.177_187del11 (p.Glu60AlafsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 226260 control chromosomes. c.177_187del11 has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000586702	SCV000740078	pathogenic	Cardiovascular phenotype	2021-11-02	criteria provided, single submitter	clinical testing	The c.177_187del11 pathogenic mutation, located in coding exon 2 of the MYBPC3 gene, results from a deletion of 11 nucleotides at nucleotide positions 177 to 187, causing a translational frameshift with a predicted alternate stop codon (p.E60Afs*49). This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J Am Coll Cardiol, 2004 Nov;44:1903-10; Zimmerman RS et al. Genet Med, 2010 May;12:268-78; Valente AM et al. Circ Cardiovasc Genet, 2013 Jun;6:230-7; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Ho CY et al. JACC Heart Fail, 2015 Feb;3:180-8; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:[ePub ahead of print]; Walsh R et al. Genet Med, 2017 02;19:192-203; Lahrouchi N et al. Eur J Hum Genet, 2020 01;28:17-22). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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.
Heart Center, Academic Medical Center Amsterdam	RCV000850018	SCV000992160	likely pathogenic	Left ventricular noncompaction 10	2018-12-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001188337	SCV001355374	pathogenic	Cardiomyopathy	2019-10-28	criteria provided, single submitter	clinical testing	This variant deletes 11 nucleotides in exon 2 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 23690394, 24510615, 25543971, 25611685, 26914223, 27532257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258108	SCV001434958	pathogenic	Hypertrophic cardiomyopathy 4	2019-02-21	criteria provided, single submitter	clinical testing	The c.177_187del (p.Glu60Alafs*49) variant in the MYBPC3 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals affected with HCM, DCM or ARVC (PMID 20474083, 24510615, 25611685, 26914223,27532257) and has never been reported in general population databases. Therefore, this c.177_187del (p.Glu60Alafs*49) variant in the MYBPC3 gene is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001188337	SCV002042139	pathogenic	Cardiomyopathy	2020-07-07	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447480	SCV004175414	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2022-09-06	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000461041	SCV001430858	pathogenic	Hypertrophic cardiomyopathy	2015-07-01	no assertion criteria provided	research	MYBPC3 Glu60Alafs*49 has been observed previously >10 probands with HCM (Walsh et al., 2017; Kapplinger et al., 2014) and has also been reported in a DCM case (Zimmerman et al, 2010). It is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this MYBPC3 Glu60Alafs*49 in a HCM proband and the variant was found to segregate to two affected family members (Ingles et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been seen reported in more than 10 unrelated HCM probands (PS4) and is rare in the general population (PM2), therefore we classify MYBPC3 Glu60Alafs*49 as "Pathogenic".