16-11553576-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001136472.2(LITAF):c.334G>A(p.Gly112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001136472.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461860Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727226
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 1C Pathogenic:7Other:1
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. -
Criteria applied: PS4,PS3_MOD,PM2_SUP,PM5_SUP,PP1,PP2,PP3 -
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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. -
Variant summary: LITAF c.334G>A (p.Gly112Ser) results in a non-conservative amino acid change located in the LITAF domain (IPR006629) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251186 control chromosomes (gnomAD). c.334G>A has been reported in the literature in several individuals and families affected with Charcot-Marie-Tooth disease type 1C (e.g. Street_2003, Jerath_2017, Park_2022). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated reduced secretion of LITAF in exosomes (Zhu_2013), which was consistent with the intracellular mislocalization of the mutant protein from the late endosome/lysosome to the mitochondria (Lacerda_2014). The following publications have been ascertained in the context of this evaluation (PMID: 12525712, 28164329, 35608774, 23576546, 25058650). ClinVar contains an entry for this variant (Variation ID: 6057). Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:4
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) -
This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23576546, 25058650) -
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Charcot-Marie-Tooth disease Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at