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

gnomAD frequency: 0.00001  dbSNP: rs753334568

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684823	SCV000543162	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-11-03	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 gene product 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	2024-07-24	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; Liang H et al. Heliyon. 2024 Apr;10(8):e29637). 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, this alteration is predicted to be deleterious by in silico analysis. 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003988827	SCV004805328	likely pathogenic	Dilated cardiomyopathy 1G	2024-03-25	criteria provided, single submitter	research
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586554	SCV005038531	likely pathogenic	Hereditary inclusion-body myopathy	2024-03-01	criteria provided, single submitter	research	PM1+PM2+PP1+PP2+PP3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000119025	SCV005399659	pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism. (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene that result in a premature truncating codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.001 (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions or uninformative conservation. (I) 0600 - Variant is located in the annotated C-terminal A-band and the exon has a PSI score of 100% (PMID: 25589632). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic in ClinVar and in over five unrelated individuals with hereditary myopathy with early respiratory failure in homozygous and heterozygous state, including de novo occurrence (PMID:23606733, PMID: 23486992, PMID: 25500009, PMID: 34670883, PMID: 34839411, PMID: 35741838, PMID: 33449170, PMID: 22526018, PMID: 28256728). Heterozygous individuals were reported to have a milder phenotype, subclinical disease or were unaffected, suggesting this variant exhibits variable expressivity and reduced penetrance (PMID:23606733, PMID: 23486992). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies suggest that this variant impacts protein folding (PMID: 24636144, PMID: 33449170). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Centre For Genomic Medicine, NCGM	RCV000119025	SCV005439083	pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure	2023-06-22	criteria provided, single submitter	clinical testing	The missense variant c.95195C>T p.Pro31732Leu in the TTN gene has been reported previously in heterozygous state in individuals affected with Hereditary myopathy with early respiratory failure. Experimental studies have shown that this missense change affects TTN function Algahtani et al., 2019; Hedberg et al., 2014. This variant is located in the A band of TTN. Variants in this region may be relevant for cardiac or neuromuscular disorders Roberts et al., 2015; Ceyhan-Birsoy et al., 2013. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/ Likely pathogenic. The amino acid Pro at position 31732 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence Polyphen, SIFT and MutationTaster predicts conflicting evidence on protein structure and function for this variant. The reference amino acid change at this position on the TTN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000727672	SCV005620757	likely pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with hereditary myopathy with early respiratory failure (HMERF). Variable expressivity and reduced penetrance was also reported. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Results were insufficient to demonstrate an effect on protein function related to disease. (PMID: 24636144, 33449170) This variant is also referred to as p.Pro22859Leu or p.Pro30091Leu in published literature.
GeneReviews	RCV000119025	SCV000153727	not provided	Myopathy, myofibrillar, 9, with early respiratory failure		no assertion provided	literature only