Submissions for variant NM_001267550.2(TTN):c.107105C>T (p.Pro35702Leu)

gnomAD frequency: 0.00008  dbSNP: rs772957495

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727225	SCV000237972	likely benign	not provided	2018-07-06	criteria provided, single submitter	clinical testing
Invitae	RCV000544128	SCV000642610	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-06-09	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727225	SCV000706745	uncertain significance	not provided	2018-06-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764291	SCV000895310	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2018-10-31	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852484	SCV000995179	uncertain significance	Hypertrophic cardiomyopathy	2018-10-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415797	SCV002678586	uncertain significance	Cardiovascular phenotype	2018-11-08	criteria provided, single submitter	clinical testing	The p.P26637L variant (also known as c.79910C>T), located in coding exon 187 of the TTN gene, results from a C to T substitution at nucleotide position 79910. The proline at codon 26637 is replaced by leucine, an amino acid with similar properties. This variant (reported as p.P35702L, c.107105C>T) was detected in a cardiomyopathy cohort; however, clinical details were not provided (Verhagen JMA et al. Eur J Hum Genet. 2018;26:1603-1610). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469051	SCV002766517	uncertain significance	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: TTN c.99401C>T (p.Pro33134Leu) results in a non-conservative amino acid change located in the M band region of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 246726 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00015 vs 0.00039), allowing no conclusion about variant significance. c.99401C>T has been reported in the literature in individuals from DCM cohorts (examples: Guelly_2021 and Verhagen_2018). At-least one publication reported this variant as likely benign (Guelly_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000727225	SCV003820238	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing