Submissions for variant NM_032588.4(TRIM63):c.739C>T (p.Gln247Ter)

dbSNP: rs148395034

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208240	SCV000264267	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-03-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623023	SCV000742685	pathogenic	Inborn genetic diseases	2024-03-14	criteria provided, single submitter	clinical testing	The c.739C>T (p.Q247*) alteration, located in coding exon 5 of the TRIM63 gene, consists of a C to T substitution at nucleotide position 739. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 247. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.068% (192/282876) total alleles studied. The highest observed frequency was 0.81% (84/10370) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and compound heterozygous with another TRIM63 variant in multiple individuals with features consistent with TRIM63-related hypertrophic cardiomyopathy (Olivé, 2015; Jokela, 2019; Salazar-Mendiguchía, 2020; Andreeva, 2022). Induced expression of the TRIM63 p.Q247* alteration in the mouse heart was associated with cardiac hypertrophy, activation of the MTOR-S6K and calcineurin pathways, and expression of hypertrophic markers, which were normalized on turning off expression of the mutant protein (Chen, 2012). Functional analysis of the variant in HeLa cells and cardiac myocytes indicated a defect in E3 ligase activity as revealed by impaired auto-ubiquitination as well as ubiquitination and subsequent degradation of TRIM63 substrates, MYH6 and MYBPC3 (Chen, 2012). However it is important to note that these expression studies were performed using a cDNA construct which likely has different physiological effects than the genomic fragment (dominant negative vs. loss of function). Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000873634	SCV001015664	likely benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	RCV000850351	SCV001749989	uncertain significance	Hypertrophic cardiomyopathy	2021-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208240	SCV003844729	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: TRIM63 c.739C>T (p.Gln247X) 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. The variant allele was found at a frequency of 0.0007 in 251478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TRIM63 causing Hypertrophic Cardiomyopathy (0.0007 vs 0.005, assuming autosomal recessive inheritance), allowing no conclusion about variant significance. c.739C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Chen_2013, Olive_2015, Jokela_2019, Salazar-Mendiguchia_2020, Andreeva_2022), primarily affecting homozygous and compound heterozygous individuals. Confirmed heterozygous carriers were unaffected (e.g. Ploski_2014, Olive_2015, Salazar-Mendiguchia_2020, Andreeva_2022). In vitro analysis of the variant in HeLa cells showed the variant completely abolished normal ubiquitination activity, which resulted in elevated levels of MYH6 and MYBPC3 levels (Chen_2013). In mice, transgenic 247* animals all showed evidence of ventricular wall thickening, which was reversed when the transgene was turned off (Chen_2013). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as pathogenic, two as uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genomics, Clalit Research Institute, Clalit Health Care	RCV000850351	SCV004801726	pathogenic	Hypertrophic cardiomyopathy	2024-03-21	criteria provided, single submitter	clinical testing	Frequency: The variant is rare, observed in 192 alleles out of 282,876 (0.067874%) in the gnomAD2 reference population dataset (PM2_support). Frequency among cases: This variant has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (PMID:24436435 , 32451364) (PS4). Variant type: Null variant in a gene where loss of function is probably mechanism of disease (PVS1). Clinical evidence: This variant has previously been described in ClinVar (VCV222849) with the following classifications: LB (1) / VUS (2) / P (1) / LP (1). Gene coverage: 100% of TRIM63 is covered with at least 10x.
Institute of Human Genetics, Medical University Innsbruck	RCV000208240	SCV005044888	likely pathogenic	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Wuerzburg	RCV000850351	SCV000992527	likely pathogenic	Hypertrophic cardiomyopathy		no assertion criteria provided	clinical testing