Submissions for variant NM_006070.6(TFG):c.1006C>T (p.Pro336Ser)

gnomAD frequency: 0.00001  dbSNP: rs371681149

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218596	SCV000279888	uncertain significance	not provided	2016-02-26	criteria provided, single submitter	clinical testing	The P336S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P336S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685206	SCV000812679	uncertain significance	Hereditary motor and sensory neuropathy, Okinawa type; Hereditary spastic paraplegia 57	2023-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 336 of the TFG protein (p.Pro336Ser). This variant is present in population databases (rs371681149, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TFG-related conditions. ClinVar contains an entry for this variant (Variation ID: 234835). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002516206	SCV003638393	uncertain significance	Inborn genetic diseases	2021-08-23	criteria provided, single submitter	clinical testing	The c.1006C>T (p.P336S) alteration is located in exon 8 (coding exon 7) of the TFG gene. This alteration results from a C to T substitution at nucleotide position 1006, causing the proline (P) at amino acid position 336 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.