ClinVar Miner

Submissions for variant NM_006070.6(TFG):c.854C>T (p.Pro285Leu) (rs207482230)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218755 SCV000279619 pathogenic not provided 2016-02-29 criteria provided, single submitter clinical testing The P285L missense variant in the TFG gene has been previously reported to segregate with proximal hereditary motor and sensory neuropathy (HMSN-P) in several large families (Lee et al., 2013, Ishiura et al., 2012, Alavi et al., 2015). Functional studies demonstrate the P285L disrupts the protein and leads to inclusion body formation in cultured cells (Ishiura et al., 2012). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P285L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000030736 SCV000292367 pathogenic Hereditary motor and sensory neuropathy, Okinawa type 2015-08-18 criteria provided, single submitter research This variant has been previously reported as disease-causing and was found in an individual with peripheral neuropathy.
Invitae RCV000642397 SCV000764067 pathogenic Hereditary motor and sensory neuropathy, Okinawa type; Spastic paraplegia 57, autosomal recessive 2018-07-25 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 285 of the TFG protein (p.Pro285Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) in multiple families (PMID: 22883144, 23553329, 25725944). ClinVar contains an entry for this variant (Variation ID: 37089). Experimental studies have shown that this missense change leads to cytoplasmic aggregation of TDP-43 (PMID: 22883144) and impacts the ubiquitin-proteasome system (PMID: 24613659, 28196470). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000030736 SCV001136563 pathogenic Hereditary motor and sensory neuropathy, Okinawa type 2019-05-28 criteria provided, single submitter clinical testing
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory,Koc University RCV001095428 SCV001251006 likely pathogenic Amyotrophic Lateral Sclerosis with Sensory Neuropathy 2020-03-31 criteria provided, single submitter research
OMIM RCV000030736 SCV000053397 pathogenic Hereditary motor and sensory neuropathy, Okinawa type 2013-05-01 no assertion criteria provided literature only

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