Submissions for variant NM_001267550.2(TTN):c.95195C>T (p.Pro31732Leu)

gnomAD frequency: 0.00001  dbSNP: rs753334568

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000684823	SCV000543162	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31732 of the TTN protein (p.Pro31732Leu). This variant is present in population databases (rs753334568, gnomAD 0.003%). This missense change has been observed in individual(s) with hereditary myopathy with early respiratory failure (HMERF) (PMID: 22526018, 23486992, 23606733, 25500009). In at least one individual the variant was observed to be de novo. This variant is also known as c.90272C>T (p.Pro30091Leu) and c.68576C>T (p.Pro22859Leu). ClinVar contains an entry for this variant (Variation ID: 132137). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TTN function (PMID: 24636144). This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000727672	SCV000854982	pathogenic	not provided	2017-12-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727672	SCV001248005	pathogenic	not provided	2018-12-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000727672	SCV001446810	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000727672	SCV002022468	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000727672	SCV002503099	likely pathogenic	not provided	2021-12-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492403	SCV002791108	pathogenic	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	2021-08-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000727672	SCV004014222	pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	Identified in a patient with Lambert-Eaton Myasthenic Syndrome (LEMS) who also harbored a pathogenic variant in the CACNA1S gene (Cerino et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies indicates this variant results in an insoluble protein due to improper folding (Hedburg et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22526018, 25500009, 23486992, 23446887, 34839411, 24636144, 35741838, 32039858, 34670883)
Ambry Genetics	RCV003343647	SCV004066464	likely pathogenic	Cardiovascular phenotype	2023-06-16	criteria provided, single submitter	clinical testing	The p.P22667L variant (also known as c.68000C>T), located in coding exon 170 of the TTN gene, results from a C to T substitution at nucleotide position 68000. The proline at codon 22667 is replaced by leucine, an amino acid with similar properties. This variant (also referred to as p.P31732L and p.P30091L) has been detected in the homozygous and heterozygous states, including a de novo occurrence, in individuals with skeletal muscle and/or respiratory issues consistent with hereditary myopathy with early respiratory failure (HMERF). Homozygous individuals tended to be more severely affected, and not all heterozygous individuals were affected, suggesting this variant exhibits variable expressivity and reduced penetrance (Vasli N et al. Acta Neuropathol., 2012 Aug;124:273-83; Yue D et al. Neuromuscul. Disord., 2015 Feb;25:172-6; Palmio J et al. J Neurol Neurosurg Psychiatry, 2014 Mar;85:345-53; Pfeffer G et al. J. Neurol. Neurosurg. Psychiatry, 2014 Mar;85:331-8; Cerino M et al. Muscle Nerve, 2017 Nov;56:993-997; Savarese M et al. J Neuromuscul Dis, 2020;7:153-166; Rees M et al. Acta Neuropathol, 2021 Mar;141:431-453; Cerino M et al. Genes (Basel), 2022 Jun;13). Functional studies suggest this variant may be destabilizing and impact protein folding (Hedberg C et al. Neuromuscul. Disord. 2014 May;24(5):373-9; Rees M et al. Acta Neuropathol, 2021 Mar;141:431-453). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is likely pathogenic for hereditary myopathy with early respiratory failure; however, the association of this alteration with cardiomyopathy is unknown.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987364	SCV004804343	pathogenic	Primary familial dilated cardiomyopathy	2024-01-09	criteria provided, single submitter	clinical testing	Variant summary: TTN c.87491C>T (p.Pro29164Leu) results in a non-conservative amino acid change located in the A-band domain 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 1.2e-05 in 248136 control chromosomes (gnomAD). c.87491C>T has been reported in the literature in multiple individuals with characteristic features of hereditary myopathy with early respiratory failure (Palmio_2013, Yue_2014, Hedberg_2014, Cerino_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in impaired protein solubility (Hedberg_2014). The following publications have been ascertained in the context of this evaluation (PMID: 35741838, 24231549, 23606733, 25500009). ClinVar contains an entry for this variant (Variation ID: 132137). Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003988827	SCV004805328	likely pathogenic	Dilated cardiomyopathy 1G	2024-03-25	criteria provided, single submitter	research
GeneReviews	RCV000119025	SCV000153727	not provided	Myopathy, myofibrillar, 9, with early respiratory failure		no assertion provided	literature only