Submissions for variant NM_001267550.2(TTN):c.82754C>A (p.Ser27585Tyr)

gnomAD frequency: 0.00010  dbSNP: rs72648215

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000725384	SCV000237632	likely benign	not provided	2021-06-09	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222951	SCV000272774	uncertain significance	not specified	2014-12-18	criteria provided, single submitter	clinical testing	The p.Ser25017Tyr variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 11/67626 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72648215). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Ser25017Tyr variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234626	SCV000286864	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-02-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725384	SCV000700958	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725384	SCV003825491	uncertain significance	not provided	2019-12-24	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002227935	SCV002507282	likely pathogenic	Tip-toe gait		flagged submission	clinical testing	Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
PreventionGenetics, part of Exact Sciences	RCV004537556	SCV004742649	uncertain significance	TTN-related disorder	2024-02-04	no assertion criteria provided	clinical testing	The TTN c.82754C>A variant is predicted to result in the amino acid substitution p.Ser27585Tyr. This variant was reported in a dilated cardiomyopathy cohort; however, no additional studies were performed to help assess the pathogenicity of this variant (Begay et al. 2015. PubMed ID: 26567375). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.