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

dbSNP: rs207482230

Total submissions: 7

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; Hereditary spastic paraplegia 57	2023-06-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TFG function (PMID: 22883144, 24613659, 28196470). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TFG protein function. ClinVar contains an entry for this variant (Variation ID: 37089). This missense change has been observed in individuals with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) (PMID: 22883144, 23553329, 25725944). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs207482230, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the TFG protein (p.Pro285Leu).
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
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251934	SCV002523397	likely pathogenic	See cases	2019-04-05	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PM2, PP1
OMIM	RCV000030736	SCV000053397	pathogenic	Hereditary motor and sensory neuropathy, Okinawa type	2013-05-01	no assertion criteria provided	literature only