Submissions for variant NM_001267550.2(TTN):c.90370G>T (p.Glu30124Ter)

dbSNP: rs1553539995

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522951	SCV000620489	likely pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	Identified in patients with DCM and LV hypertrabeculation (LVHT) in published literature (PMID: 28798025, 29540472, 32880476); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 22335739, 32880476, 28798025, 29540472)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778991	SCV002014882	likely pathogenic	Primary familial dilated cardiomyopathy	2021-10-11	criteria provided, single submitter	clinical testing	Variant summary: TTN c.82666G>T (p.Glu27556X) 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, which are commonly known mechanisms for disease. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (PMID: 22335739, PMID: 24503780) and/or are located in an exon that is highly expressed in the heart (PMID: 25589632). The variant was absent in 248466 control chromosomes. c.82666G>T has been reported in the literature in individuals affected with DCM or LVHT including in one case where segregation was reported but specific family details were not described (Miszalski-Jamka_2017, Hazebroek_2018, Verdonschot_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Center for Human Genetics, University of Leuven	RCV003237349	SCV002817405	pathogenic	Primary dilated cardiomyopathy	2022-12-31	criteria provided, single submitter	clinical testing
Invitae	RCV003766961	SCV004569186	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu30124*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 28798025, 32880476). This variant is also known as c.G85447T:p.E28483X. ClinVar contains an entry for this variant (Variation ID: 451748). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.