ClinVar Genomic variation as it relates to human health
NM_001136472.2(LITAF):c.334G>A (p.Gly112Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001136472.2(LITAF):c.334G>A (p.Gly112Ser)
Variation ID: 6057 Accession: VCV000006057.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.13 16: 11553576 (GRCh38) [ NCBI UCSC ] 16: 11647432 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001136472.2:c.334G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001129944.1:p.Gly112Ser missense NM_001136473.1:c.334G>A NP_001129945.1:p.Gly112Ser missense NM_004862.4:c.334G>A NP_004853.2:p.Gly112Ser missense NR_024320.2:n.468G>A non-coding transcript variant NC_000016.10:g.11553576C>T NC_000016.9:g.11647432C>T NG_009008.1:g.38375G>A LRG_253:g.38375G>A LRG_253t1:c.334G>A LRG_253p1:p.Gly112Ser Q99732:p.Gly112Ser - Protein change
- G112S
- Other names
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- Canonical SPDI
- NC_000016.10:11553575:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LITAF | No evidence available | No evidence available |
GRCh38 GRCh37 |
280 | 310 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000006429.23 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 3, 2023 | RCV000235719.7 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001173620.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 30, 2022 | RCV002321474.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 26, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000255673.3
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2018 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001336720.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
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Pathogenic
(Jan 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 1C
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428484.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(May 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 1C
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579030.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PP1_STR, PS3_MOD, PS4_MOD, PM1, PM5, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Apr 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224112.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Number of individuals with the variant: 4
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Pathogenic
(Nov 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 1C
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563577.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The LITAF c.334G>A; p.Gly112Ser variant (rs104894519) is reported in the literature in several large families affected with Charcot-Marie-Tooth disease type 1C (Bennett 2004, Klein 2014, … (more)
The LITAF c.334G>A; p.Gly112Ser variant (rs104894519) is reported in the literature in several large families affected with Charcot-Marie-Tooth disease type 1C (Bennett 2004, Klein 2014, Latour 2006, Park 2022, Potulska-Chromik 2012, Saifi 2005, Street 2003). This variant is also reported in ClinVar (Variation ID: 6057), but is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.820), and functional analyses of the variant protein show disrupted protein localization (Lacerda 2014, Zhu 2013). Based on available information, this variant is considered to be pathogenic. References: Bennett CL et al. SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve. Ann Neurol. 2004 May;55(5):713-20. PMID: 15122712. Klein CJ et al. Application of whole exome sequencing in undiagnosed inherited polyneuropathies. J Neurol Neurosurg Psychiatry. 2014 Nov;85(11):1265-72. PMID: 24604904. Lacerda AF et al. LITAF mutations associated with Charcot-Marie-Tooth disease 1C show mislocalization from the late endosome/lysosome to the mitochondria. PLoS One. 2014 Jul 24;9(7):e103454. PMID: 25058650. Latour P et al. SIMPLE mutation analysis in dominant demyelinating Charcot-Marie-Tooth disease: three novel mutations. J Peripher Nerv Syst. 2006 Jun;11(2):148-55. PMID: 16787513. Park J et al. Identification and clinical characterization of Charcot-Marie-Tooth disease type 1C patients with LITAF p.G112S mutation. Genes Genomics. 2022 Aug;44(8):1007-1016. PMID: 35608774. Potulska-Chromik A et al. Charcot-Marie-Tooth type 1C disease coexisting with progressive multiple sclerosis: a study of an overlapping syndrome. Folia Neuropathol. 2012;50(4):369-74. PMID: 23319192. Saifi GM et al. SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum Mutat. 2005 Apr;25(4):372-83. PMID: 15776429. Street VA et al. Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology. 2003 Jan 14;60(1):22-6. PMID: 12525712. Zhu H et al. Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Mol Biol Cell. 2013 Jun;24(11):1619-37, S1-3. PMID: 23576546. (less)
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Pathogenic
(Dec 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002606147.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.334G>A (p.G112S) alteration is located in exon 3 (coding exon 2) of the LITAF gene. This alteration results from a G to A substitution … (more)
The c.334G>A (p.G112S) alteration is located in exon 3 (coding exon 2) of the LITAF gene. This alteration results from a G to A substitution at nucleotide position 334, causing the glycine (G) at amino acid position 112 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in numerous individuals or families with inherited peripheral neuropathy phenotypes, such as Charcot-Marie-Tooth disease (Street, 2003; Bennett, 2004; Saifi, 2005; Latour, 2006; Potulska-Chromik, 2012; Klein, 2014; Jerath, 2017; Khosa, 2020; Vogt, 2020; Volodarsky, 2021). Another alteration at the same codon, c.335G>C (p.G112A), has been detected in an individual with Charcot-Marie-Tooth 1C (Guimarães-Costa, 2017). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrated that the p.G112S alteration reduced secreted LITAF in exosomes (Zhu, 2013) and mislocalized from the late endosome/lysosome to the mitochondria (Lacerda, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Feb 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000293113.8
First in ClinVar: Jul 24, 2016 Last updated: Dec 19, 2017 |
Comment:
Published functional studies demonstrate that G112S alters the intracellular localization of LITAF protein as well as the production of exosomes (Zhu et al., 2013; Lacerda … (more)
Published functional studies demonstrate that G112S alters the intracellular localization of LITAF protein as well as the production of exosomes (Zhu et al., 2013; Lacerda et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20301384, 15776429, 12525712, 27549087, 28981955, 15786462, 1407588, 2239969, 23319192, 23576546, 25058650, 15122712, 24604904, 32399692, 33359733, 30373780, 31211173, 31827005, 32665875, 28211240, 32376792) (less)
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 1C
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000253888.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 112 of the LITAF protein (p.Gly112Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 112 of the LITAF protein (p.Gly112Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LITAF-related conditions (PMID: 12525712, 15122712, 15776429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6057). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects LITAF function (PMID: 23576546, 25058650). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 2005)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, TYPE 1C
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026612.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 14, 2020 |
Comment on evidence:
In a family (K1551) segregating CMT1C (601098), Street et al. (2003) identified a 334G-A transition in exon 3 of the LITAF gene, resulting in a … (more)
In a family (K1551) segregating CMT1C (601098), Street et al. (2003) identified a 334G-A transition in exon 3 of the LITAF gene, resulting in a gly112-to-ser (G112S) substitution. The family had previously been reported by Chance et al. (1990, 1992). In affected members of a family with CMT1C and a patient with sporadic CMT1C, Saifi et al. (2005) identified the G112S mutation. In a 2-year-old boy with severe demyelinating CMT, Meggouh et al. (2005) identified compound heterozygosity for 2 mutations: the G112S mutation in LITAF and a PMP22 duplication (601097.0001), which is the most common cause of CMT1A (118220). Each parent was heterozygous for 1 of the mutations, and each had pes cavus and reduced nerve conduction velocities consistent with mild CMT. Meggouh et al. (2005) concluded that the cooccurrence of both mutations resulted in the more severe phenotype in the proband. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Charcot-Marie-Tooth disease type 1C
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760355.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Charcot-Marie-Tooth disease type 1C
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000055877.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. | Volodarsky M | Journal of medical genetics | 2021 | PMID: 32376792 |
A Rare Case of Charcot-Marie-Tooth Disease Type 1C With an Unusual Presentation. | Khosa S | Cureus | 2020 | PMID: 32665875 |
Screening for genetic mutations in patients with neuropathy without definite etiology is useful. | Vogt B | Journal of neurology | 2020 | PMID: 32399692 |
Phenotypic spectrum of Charcot-Marie-Tooth disease due to LITAF/SIMPLE mutations: a study of 18 patients. | Guimarães-Costa R | European journal of neurology | 2017 | PMID: 28211240 |
Charcot-Marie-Tooth disease type 1C: Clinical and electrophysiological findings for the c.334G>a (p.Gly112Ser) Litaf/Simple mutation. | Jerath NU | Muscle & nerve | 2017 | PMID: 28164329 |
Improving diagnosis of inherited peripheral neuropathies through gene panel analysis. | Laššuthová P | Orphanet journal of rare diseases | 2016 | PMID: 27549087 |
Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2015 | PMID: 20301384 |
LITAF mutations associated with Charcot-Marie-Tooth disease 1C show mislocalization from the late endosome/lysosome to the mitochondria. | Lacerda AF | PloS one | 2014 | PMID: 25058650 |
Application of whole exome sequencing in undiagnosed inherited polyneuropathies. | Klein CJ | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 24604904 |
Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. | Zhu H | Molecular biology of the cell | 2013 | PMID: 23576546 |
Charcot-Marie-Tooth type 1C disease coexisting with progressive multiple sclerosis: a study of an overlapping syndrome. | Potulska-Chromik A | Folia neuropathologica | 2012 | PMID: 23319192 |
Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease. | Meggouh F | Annals of neurology | 2005 | PMID: 15786462 |
SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. | Saifi GM | Human mutation | 2005 | PMID: 15776429 |
Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. | Street VA | Neurology | 2003 | PMID: 12525712 |
Analysis of the DNA duplication 17p11.2 in Charcot-Marie-Tooth neuropathy type 1 pedigrees: additional evidence for a third autosomal CMT1 locus. | Chance PF | Neurology | 1992 | PMID: 1407588 |
Genetic linkage and heterogeneity in type I Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy type I). | Chance PF | American journal of human genetics | 1990 | PMID: 2239969 |
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Text-mined citations for rs104894519 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.