Submissions for variant NM_001267550.2(TTN):c.38442dup (p.Pro12815fs)

dbSNP: rs752101551

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV001353359	SCV001548514	pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure	2021-03-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001555419	SCV001776837	pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing	Has not been previously reported in peer-reviewed literature as pathogenic or benign to our knowledge. However, in an abstract by Gruber et al. (2020), c.38442dupA was identified with a second TTN variant, phase unknown, in an individual with features of a congenital titinopathy; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a region of the TTN gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27625338, 27869827)
AiLife Diagnostics, AiLife Diagnostics	RCV001555419	SCV002502413	uncertain significance	not provided	2021-09-28	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003136021	SCV003806892	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2022-07-04	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong
PreventionGenetics, part of Exact Sciences	RCV003918872	SCV004732668	pathogenic	TTN-related condition	2023-11-21	criteria provided, single submitter	clinical testing	The TTN c.38442dupA variant is predicted to result in a frameshift and premature protein termination (p.Pro12815Thrfs*37). This variant has been reported in the compound heterozygous state with a nonsense variant in a neonate with severe titinopathy (Family B in Alkhunaizi et al. 2023. PubMed ID: 36495114). At PreventionGenetics we have observed this variant in the compound heterozygous state with another protein truncating TTN variant in two other patients with congenital titinopathy clinical features (https://www.nmd-journal.com/article/S0960-8966(20)30296-0/abstract). A similar nearby homozygous deletion (c.38661_38665delGAAA) in this region has been reported in a patient with high arched palate, severe axial hypotonia, distal contractures, equinovarus feet, bilateral dislocated hips, and spiral fractures of both humerus bones and the left femur (Fernández-Marmiesse et al. 2017. PubMed ID: 28040389). 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 these 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). In summary, we categorize the c.38442dup as pathogenic for autosomal recessive TTN-related myopathy. Of note, the c.38442dup variant resides in a highly homologous region of the TTN gene where NGS analysis may have limitations. However, unique PCR primers were designed and confirmed this variant via Sanger sequencing.