Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Neuro |
RCV000754743 | SCV000882632 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2J | 2018-10-08 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV004527768 | SCV001451499 | pathogenic | TTN-related disorder | 2019-03-20 | criteria provided, single submitter | clinical testing | The TTN c.38737G>T (p.Glu12913Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000029 in the Latino population of the Genome Aggregation Database though this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. This genomic position is predicted to be present in both cardiac and muscle isoforms. Based on the truncating nature of the variant, its rarity, and identification in trans with a pathogenic variant, the p.Glu12913Ter variant is classified as pathogenic for TTN-related disorders. |
| Gene |
RCV002284435 | SCV002574382 | likely pathogenic | not provided | 2022-06-13 | criteria provided, single submitter | clinical testing | Previously reported in the heterozygous state in an individual with congenital myopathy; however, parental studies were not reported (Gonzalaz-Queraded et al., 2020); Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); This variant is associated with the following publications: (PMID: 32403337, 23975875) |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV004527768 | SCV005874112 | pathogenic | TTN-related disorder | 2024-10-30 | criteria provided, single submitter | clinical testing | PVS1, PM2, PM3 |
| Prevention |
RCV004527768 | SCV004730004 | likely pathogenic | TTN-related disorder | 2023-12-02 | no assertion criteria provided | clinical testing | The TTN c.38737G>T variant is predicted to result in premature protein termination (p.Glu12913*). This variant has been reported in the heterozygous state in an individual with congenital hypertonia and cardiomyopathy and a second TTN variant was not identified (Supplemental Table, Gonzalez-Quereda L et al. 2020. PubMed ID: 32403337). RNAseq studies from heart tissue indicate this exon is not commonly included in TTN mRNA transcripts (PSI of 3%-5%; Roberts A.M. et al. 2015. PMID: 25589632;https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is less likely to cause autosomal dominant TTN-related disorders (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). This variant is found in an exon specific to the TTN metatranscript and is not included in the skeletal muscle isoform (NM_133378.4); however, many other protein truncating variants in metatranscript-only exons have been recently observed in severe recessive congenital titinopathies (Bryen et al. 2020. PubMed ID: 31660661; Oates et al. 2018. PubMed ID: 29691892; Chervinsky et al. 2018. PubMed ID: 29575618). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Taken together, we classify the c.38737G>T (p.Glu12913*) variant as likely pathogenic for autosomal recessive titinopathies and as uncertain for autosomal dominant TTN-related disorders. |