NM_001267550.2(TTN):c.95195C>T (p.Pro31732Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Nov 17, 2023
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:: RCV000727672.49

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000854982	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 3, 2017)	germline	clinical testing	Citation Link,
SCV001248005	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2018)	germline	clinical testing	Citation Link,
SCV001446810	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002022468	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002503099	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 14, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23486992, 24636144, 32039858, 22526018, 25500009, 25741868
SCV004014222	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 22, 2023)	germline	clinical testing	Citation Link,
SCV005620757	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	likely pathogenic (Nov 17, 2023)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 35741838, 33449170, 32039858, 28256728, 25500009, 24636144, 24231549, 23606733, 23486992, 22526018, 30365001, 34670883, 34839411, 23446887, 28781516, 25253871, 24578547, 24569025, 24271327, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population.

Cerino M, González-Hormazábal P, Abaji M, Courrier S, Puppo F, Mathieu Y, Trangulao A, Earle N, Castiglioni C, Díaz J, Campero M, Hughes R, Vargas C, Cortés R, Kleinsteuber K, Acosta I, Urtizberea JA, Lévy N, Bartoli M, Krahn M, Jara L, Caviedes P, et al.

Genes (Basel). 2022 Jun 16;13(6). doi: 10.3390/genes13061076.

PubMed [citation]

PMID:: 35741838
PMCID:: PMC9223019

See all PubMed Citations (21)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000854982.2

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

#	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		1	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001248005.38

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

#	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		1	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446810.2

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

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

From Revvity Omics, Revvity, SCV002022468.4

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

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002503099.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

#	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		1	not provided	not provided	not provided

From GeneDx, SCV004014222.1

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

Description

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)

#	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 Athena Diagnostics, SCV005620757.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

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.

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

Last Updated: Jul 6, 2026

Relating variation to medicine