Submissions for variant NM_000256.3(MYBPC3):c.1227-2A>G

gnomAD frequency: 0.00001  dbSNP: rs730880531

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158068	SCV000208003	pathogenic	not provided	2015-08-18	criteria provided, single submitter	clinical testing	This variant is denoted MYBPC3 c.1227-2 A>G at the c.DNA level. The c.1227-2 A>G mutation in the MYBPC3 gene has been previously reported in one patient with HCM (Richard P et al., 2003). This mutation destroys the canonical splice acceptor site of intron 14. The mutation is predicted to lead to either an abnormal message, which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the MYBPC3 gene have been reported in association with HCM. Furthermore, the c.1227 A>G mutation was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.1227-2 A>G in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001176296	SCV001340213	likely pathogenic	Cardiomyopathy	2019-07-02	criteria provided, single submitter	clinical testing	This variant alters the intron 14 canonical splice acceptor site of the MYBPC3 gene. Computational splicing tools predict that this variant may have a significant impact on RNA splicing. Although RNA study has not been performed to confirm the prediction, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 30297972; Kassem 2017). This variant has been identified in 1/31392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001376918	SCV001574113	likely pathogenic	Hypertrophic cardiomyopathy	2022-07-25	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 25351510). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 180925). This variant is present in population databases (rs730880531, gnomAD 0.06%). This sequence change affects an acceptor splice site in intron 14 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).
Ambry Genetics	RCV002372030	SCV002667633	likely pathogenic	Cardiovascular phenotype	2022-04-28	criteria provided, single submitter	clinical testing	The c.1227-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 15 in the MYBPC3 gene. This variant (also referred to as IVS14-2A>G) has been detected in hypertrophic cardiomyopathy cohorts; however, details were limited (Richard P et al. Circulation, 2003 May;107:2227-32; Lopes LR et al. Heart. 2015 Feb;101(4):294-301; Miller RJH et al. PLoS ONE, 2019 Jun;14:e0217612; Walsh R et al. Genome Med, 2019 01;11:5). In one family, this variant was reported to occur in the homozyous state in a proband whose heterozygous father was also affected, while several other heterozygous relatives were indicated as unaffected; however, clinical details were not provided (Kassem H.Sh. et al. EJMHG, 2017 Oct;18(4):381-387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158068	SCV000280208	likely pathogenic	not provided	2014-09-19	no assertion criteria provided	clinical testing	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. MYBPC3 IVS14-2 A>G Based on the data reviewed below we consider this variant likely disease-causing. The variant has been seen in at least 1 unrelated case of HCM. This variant has been previously reported in one patient with HCM (Richard P. et al, 2003) . Richard and colleagues studied the coding sequences of 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC, and TNNC1) in 197 unrelated index cases hypertrophic cardiomyopathy. A variant was considered a mutation on the basis of the following 3 criteria: cosegregation with affected members in the family, absence of the mutation in 200 unrelated chromosomes of healthy adult controls, and the conservation of the mutated residue among species and isoforms. This variant destroys the canonical splice acceptor site of intron 14. It is located one base pair before the 1227th coding nucleotide at the beginning of the exonThe variant is predicted to lead to either an abnormal message, which is subjected to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. Many protein-truncating variants have been reported in MYBPC3 in association with HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database), and splice variants in MYBPC3 are a well-established cause of HCM. MYBPC3 splice variants reported in association with HCM include IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A (Harvard Sarcomere Protein Gene Mutation Database, data curated previously). In total the variant has not been seen in ~6,600 published controls and individuals from publicly available population datasets. There is no variation at this location listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 7/15/13).