Submissions for variant NM_001267550.2(TTN):c.107840T>A (p.Ile35947Asn)

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000013490	SCV001149973	pathogenic	Tibial muscular dystrophy	2020-02-12	criteria provided, single submitter	clinical testing
Invitae	RCV001319595	SCV001510348	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-03-30	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change does not substantially affect TTN function (25877298 25739468). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 12654). This variant is also known as ATT>AAT change at position 293,329, I35947N, or I57N. This missense change has been observed in individual(s) with clinical features of autosomal recessive TTN-related conditions (PMID: 27796757; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant tibial muscular dystrophy (PMID: 12891679); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs281864928, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 35947 of the TTN protein (p.Ile35947Asn). 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. This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875).
OMIM	RCV000013490	SCV000033737	pathogenic	Tibial muscular dystrophy	2003-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000013490	SCV000054697	not provided	Tibial muscular dystrophy		no assertion provided	literature only

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