Submissions for variant NM_001267550.2(TTN):c.11183dup (p.Leu3729fs)

dbSNP: rs778172350

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000184376	SCV000051224	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209565	SCV000189728	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon with low levels of cardiac expression. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209565	SCV000189798	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon with low levels of cardiac expression. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
GeneDx	RCV000184376	SCV000237001	uncertain significance	not provided	2014-02-17	criteria provided, single submitter	clinical testing	c.10670dupG: p.Leu3558ThrfsX9 (L3558TfsX9) in exon 44 of the TTN gene (#NM_133437.3). The normal sequence with the base that is duplicated in braces is: CAAG{G}ACTA. The c.10670dupG variant has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. This variant causes a shift in reading frame starting at codon Leucine 3558, changing it to a Threonine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Leu3558ThrfsX9. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, c.10670dupG is located in an alternate transcript of the TTN gene where no disease-causing mutations have been reported.With the clinical and molecular information available at this time, we cannot definitively determine if c.10670dupG is a disease-causing mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s).
CeGaT Center for Human Genetics Tuebingen	RCV000184376	SCV000493693	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Moderate, PS4:Supporting
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769096	SCV000900469	uncertain significance	Cardiomyopathy	2017-06-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222432	SCV002500637	uncertain significance	not specified	2022-03-24	criteria provided, single submitter	clinical testing	Variant summary: TTN NM_133378.4: c.10303+2691dupG alters a concerved nucleotide located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is also annotated as NM_001267550.1: c.11183dupG (p.Leu3729fs) in exon 46 of meta transcript. This exon is considered as a low expression exon with a percentage spliced in (PSI) score of 4% and is therefore not considered as a constitutively expressed exon of critical relevance to TTN function. TTN truncating variants in this exon are considered to be tolerated and therefore not relevant to any of the penetrant TTN-related disorder phenotypes. The variant allele was found at a frequency of 0.0001 in 248776 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.0001 vs 0.00063), allowing no conclusion about variant significance. c.10303+2691dupG has been reported as c.11183dupG in the literature in a variety of settings such as, controls and individuals with heart failure from the UK biobank cohort (example, Choi_2020), one Dilated Cardiomyopathy (DCM) proband from a cohort that underwent reverse-parent offspring analysis (example, Jansen_2019), in one individual from a cohort of patients with early-onset artial fibrillation (example, Yoneda_2021). These report(s) do not provide unequivocal conclusions about association of the variant with penetrant TTN-related phenotypes of Dilated Cardiomyopathy/Limb-Girdle Muscular Dystrophy, Type 2J. At-least one co-occurrence with another pathogenic variant(s) has been reported in an individual from a cohort with early-onset Atrial Fibrillation (AF diagnosed before the age of 66 years)(Yoneda_2021, MYH7 c.1988G>A, p.Arg663His), although the specific clinical details were not reported. This provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.