Submissions for variant NM_000256.3(MYBPC3):c.3335_3337dup (p.Trp1112dup)

dbSNP: rs730880673

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158401	SCV000208336	uncertain significance	Cardiomyopathy	2012-09-19	criteria provided, single submitter	clinical testing	c.3335_3337dupGGT: p.Trp1112dup (W1112dup) in exon 31 of the MYBPC3 gene (NM_000256.3). The normal sequence with the bases inserted in braces is: TGGT{GGT}TCAC.The c.3335_3337dupGGT variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The c.3335_3337dupGGT variant results in an in-frame duplication of a single Tryptophan residue in a region of the protein that is well conserved across species. While no single amino acid duplications in the MYBPC3 gene have been reported as disease-causing mutations, a duplication of six amino acids (c.3742_3759dup18) has been reported in association with HCM (Watkins H et al., 1995). In summary, the clinical significance of the c.3335_3337dupGGT variant in the MYBPC3 gene is currently unknown. The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857565	SCV002136734	uncertain significance	Hypertrophic cardiomyopathy	2024-04-08	criteria provided, single submitter	clinical testing	This variant, c.3335_3337dup, results in the insertion of 1 amino acid(s) of the MYBPC3 protein (p.Trp1112dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs730880673, gnomAD 0.002%). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28790153). ClinVar contains an entry for this variant (Variation ID: 181101). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002321665	SCV002606596	uncertain significance	Cardiovascular phenotype	2020-03-16	criteria provided, single submitter	clinical testing	The c.3335_3337dupGGT variant (also known as p.W1112dup), located in coding exon 31 of the MYBPC3 gene. This variant results from an in-frame duplication of GGT at nucleotide positions 3335 to 3337. This results in the duplication of a highly conserved tryptophan residue between codons 1112 and 1113. This alteration was reported to co-occur with another MYBPC3 alteration in a family with hypertrophic cardiomyopathy (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:e001666). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000158401	SCV004358633	uncertain significance	Cardiomyopathy	2023-07-27	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication of one amino acid at exon 31 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygous state with a different pathogenic variant in the MYBPC3 gene in two related individuals, one affected with hypertrophic cardiomyopathy and one affected with sudden death (PMID: 28790153). This variant has been identified in 3/239746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001857565	SCV004836617	uncertain significance	Hypertrophic cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This variant causes an in-frame duplication of one amino acid at exon 31 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygous state with a different pathogenic variant in the MYBPC3 gene in two related individuals, one affected with hypertrophic cardiomyopathy and one affected with sudden death (PMID: 28790153). This variant has been identified in 3/239746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.