Submissions for variant NM_000256.3(MYBPC3):c.1084dup (p.Ser362fs)

dbSNP: rs730880723

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223853	SCV000208422	pathogenic	not provided	2015-08-04	criteria provided, single submitter	clinical testing	The c.1084dupA pathogenic variant in the MYBPC3 gene been reported previously in one individual with HCM, and was absent from 307 control alleles (Wang J et al., 2014). Additionally, the c.1084dupA mutation was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant causes a shift in reading frame starting at codon Serine 362, changing it to a Lysine, and creating a premature stop codon at position 28 of the new reading frame, denoted p.Ser362LysfsX28. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, other frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM and dilated cardiomyopathy (DCM) (Stenson P et al., 2014).
Invitae	RCV000456333	SCV000546441	pathogenic	Hypertrophic cardiomyopathy	2016-12-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MYBPC3 are known to be pathogenic. This particular variant has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (PMID: 25132132). This variant is also known as 1084_1085insA in the literature. This sequence change inserts 1 nucleotide in exon 12 of the MYBPC3 mRNA (c.1084dupA), causing a frameshift at codon 362. This creates a premature translational stop signal (p.Ser362Lysfs*28) and is expected to result in an absent or disrupted protein product.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223853	SCV000280205	likely pathogenic	not provided	2013-07-15	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. p.Ser362LysX28 (c.1084dupA) in the MYBPC3 gene. Given the strong evidence that frameshift variants in MYBPC3 are disease-causing we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant appears to be novel. This is a frame-shifting variant that creates a premature stop codon 5 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. While this specific variant is novel, many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are only very rarely seen in individuals without cardiomyopathy (Pan et al 2012). The variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of June 18, 2015).