Submissions for variant NM_000256.3(MYBPC3):c.2267del (p.Pro756fs)

dbSNP: rs730880651

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158360	SCV000208295	pathogenic	not provided	2023-05-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 20474083, 27532257, 10521296)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475465	SCV000546498	pathogenic	Hypertrophic cardiomyopathy	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro756Leufs*66) 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 hypertrophic cardiomyopathy (PMID: 10521296, 27532257). ClinVar contains an entry for this variant (Variation ID: 181078). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798534	SCV002042157	pathogenic	Cardiomyopathy	2022-04-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004639152	SCV005144223	pathogenic	Cardiovascular phenotype	2024-03-22	criteria provided, single submitter	clinical testing	The c.2267delC pathogenic mutation, located in coding exon 23 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 2267, causing a translational frameshift with a predicted alternate stop codon (p.P756Lfs*66). This variant was reported in multiple individuals with features consistent with hypertrophic cardiomyopathy (Moolman-Smook JC et al. Am J Hum Genet. 1999 Nov;65(5):1308-20; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786425	SCV005400078	pathogenic	Hypertrophic cardiomyopathy 4	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported multiple times as pathogenic, including in more than five unrelated individuals with HCM (cardiodb, ClinVar, PMID: 10521296). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
All of Us Research Program, National Institutes of Health	RCV000475465	SCV005429981	pathogenic	Hypertrophic cardiomyopathy	2024-07-10	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 23 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. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 10521296, 27532257, 30297972, 32841044, 33782553, 33495596, 33495597, 38489124). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001798534	SCV006061429	pathogenic	Cardiomyopathy	2024-04-05	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 23 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. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 10521296, 27532257, 30297972, 32841044, 33782553, 33495596, 33495597, 38489124). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.