NM_001267550.2(TTN):c.95195C>T (p.Pro31732Leu) AND Myopathy, myofibrillar, 9, with early respiratory failure

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 9, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000119025.8

Allele description [Variation Report for NM_001267550.2(TTN):c.95195C>T (p.Pro31732Leu)]

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

Genes:

TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

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

Other names:

Q8WZ42.4:p.Pro30091Leu

HGVS:

NC_000002.12:g.178546041G>A
NG_011618.3:g.289762C>T
NG_051363.1:g.28215G>A
NM_001256850.1:c.90272C>T
NM_001267550.2:c.95195C>TMANE SELECT
NM_003319.4:c.68000C>T
NM_133378.4:c.87491C>T
NM_133432.3:c.68375C>T
NM_133437.4:c.68576C>T
NP_001243779.1:p.Pro30091Leu
NP_001254479.2:p.Pro31732Leu
NP_003310.4:p.Pro22667Leu
NP_596869.4:p.Pro29164Leu
NP_597676.3:p.Pro22792Leu
NP_597681.4:p.Pro22859Leu
AJ277892.2:g.274436C>T
LRG_391:g.289762C>T
NC_000002.11:g.179410768G>A
NM_001267550.1:c.95195C>T
NM_003319.4:c.68000C>T
NM_133378.4:c.87491C>T

Protein change:

P22667L

Links:

dbSNP: rs753334568

Molecular consequence:

NM_001256850.1:c.90272C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.95195C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.68000C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.87491C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.68375C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.68576C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Myopathy, myofibrillar, 9, with early respiratory failure (MFM9)
Synonyms:: EDSTROM MYOPATHY; MYOPATHY, PROXIMAL, WITH EARLY RESPIRATORY MUSCLE INVOLVEMENT; Hereditary myopathy with early respiratory failure; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011362; MedGen: C1863599; Orphanet: 178464; Orphanet: 34521; OMIM: 603689

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000153727	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 23606733, 23486992, 24575448
SCV005399659	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 9, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 22526018, 23486992, 23606733, 24636144, 25500009, 25589632, 28256728, 33449170, 34670883, 34839411, 35741838, 25741868
SCV005439083	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000153727

GeneReviews

no classification provided

not provided

germline

literature only

PubMed (3)
[See all records that cite these PMIDs]

SCV005399659

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 9, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV005439083

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 22, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Hereditary Myopathy with Early Respiratory Failure..

Pfeffer G, Chinnery PF.

2014 Feb 27 [updated 2024 Dec 12]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

PubMed [citation]

PMID:: 24575448

Next generation sequencing for molecular diagnosis of neuromuscular diseases.

Vasli N, Böhm J, Le Gras S, Muller J, Pizot C, Jost B, Echaniz-Laguna A, Laugel V, Tranchant C, Bernard R, Plewniak F, Vicaire S, Levy N, Chelly J, Mandel JL, Biancalana V, Laporte J.

Acta Neuropathol. 2012 Aug;124(2):273-83. doi: 10.1007/s00401-012-0982-8. Epub 2012 Apr 18.

PubMed [citation]

PMID:: 22526018
PMCID:: PMC3400754

See all PubMed Citations (13)

Details of each submission

From GeneReviews, SCV000153727.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005399659.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005439083.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 6, 2026

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