Submissions for variant NM_006070.6(TFG):c.316C>T (p.Arg106Cys)

gnomAD frequency: 0.00001  dbSNP: rs587777175

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001038327	SCV001201792	pathogenic	Hereditary motor and sensory neuropathy, Okinawa type; Hereditary spastic paraplegia 57	2023-07-25	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: 23479643, 27492651, 30157421). 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: 100909). This missense change has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 23479643, 27492651, 29971521). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs587777175, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 106 of the TFG protein (p.Arg106Cys).
GeneDx	RCV001549766	SCV001769979	pathogenic	not provided	2021-06-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate damaging effects on protein secretion from the endoplasmic reticulum (ER), ER morphology, and mitochondrial dysfunction (Beetz et al., 2013; Harlalka et al., 2016; Slosarek et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 32488467, 30157421, 30221345, 26945032, 24954637, 27813252, 25098539, 24613659, 27601211, 27492651, 29971521, 23479643)
Ambry Genetics	RCV002321583	SCV002607724	pathogenic	Inborn genetic diseases	2020-12-18	criteria provided, single submitter	clinical testing	The p.R106C variant (also known as c.316C>T), located in coding exon 3 of the TFG gene, results from a C to T substitution at nucleotide position 316. The arginine at codon 106 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in the homozygous state in multiple unrelated families and segregates with autosomal recessive hereditary spastic paraplegia and optic nerve hypoplasia in affected relatives (Beetz C et al. Proc Natl Acad Sci U S A, 2013 Mar;110:5091-6; Harlalka GV et al. Hum Mutat, 2016 11;37:1157-1161; Kvarnung M et al. Clin Genet, 2018 12;94:528-537; Catania A et al. Neurogenetics, 2018 08;19:179-187). Functional studies with this alteration show impaired TFG protein oligomerization leading to abnormal ER function (Beetz C et al. Proc Natl Acad Sci U S A, 2013 Mar;110:5091-6; Harlalka GV et al. Hum Mutat, 2016 11;37:1157-1161; Slosarek EL et al. Cell Rep, 2018 08;24:2248-2260). Based on the supporting evidence, this variant is pathogenic for spastic paraplegia 57 (SPG57); however, the clinical significance for hereditary motor and sensory neuropathy, Okinawa type (HMSN-P) is unclear.
OMIM	RCV000087273	SCV000120136	pathogenic	Hereditary spastic paraplegia 57	2013-03-26	no assertion criteria provided	literature only
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000087273	SCV002029213	pathogenic	Hereditary spastic paraplegia 57	2021-10-05	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001549766	SCV003840131	pathogenic	not provided	2022-05-10	no assertion criteria provided	clinical testing	DNA sequence analysis of the TGF gene demonstrated a sequence change, c.316C>T, in exon 4 that results in an amino acid change, p.Arg106Cys. The p.Arg106Cys change affects a highly conserved amino acid residue located in a domain of the TFG protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg106Cys substitution. This sequence change has been described in the gnomAD database with a frequency of 0.0086% in the non-Finnish European subpopulation (dbSNP rs587777175). This pathogenic sequence change has previously been described in the homozygous state in individuals with autosomal recessive spastic paraplegia (PMID: 23479643, 27492651, 29971521). Heterozygous pathogenic variants have also been described in individuals with autosomal dominant hereditary motor and sensory neuropathy (PMID: 22883144). However, variants associated with autosomal dominant conditions appear to be located in a different region of the protein than the p.Arg106Cys substitution (PMID: 26945032). Heterozygous carriers of the p.Arg106Cys change have not been reported to be affected. The TGF cDNA reference sequence used is NM_006070.5