Submissions for variant NM_014844.5(TECPR2):c.2708C>T (p.Thr903Met)

gnomAD frequency: 0.00001  dbSNP: rs752912949

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001242457	SCV001386966	uncertain significance	Hereditary spastic paraplegia 49	2020-07-11	criteria provided, single submitter	curation	This variant has been reported compound heterozygous with the variant NM_014844.4:c.2050C>G, p.(Leu684Val) in a 15 year old girl with muscular hypotonia of the trunk and upper limbs, spastic gait, dysarthria and mild thinning of the corpus callosum in cranial MRI (PMID: 27406698). The variant is maternally inherited. The family is from Italian descent. This missense variant c.2708C>T, p.(Thr903Met) in exon 11/20 of the TECPR2 has not been reported in public mutation databases. In the general population the minor allele frequency is 0.00003980 (gnomAD). Biallelic truncating or missense variants have been described to cause "Spastic paraplegia 49, autosomal recessive" (Oz-Levi et al. Am J Hum Genet. 2012, PMID: 23176824). Multiple in silico-tools predict this variant as damaging. Taken together, we classify this variant as of unknown significance based on the ACMG recommendations (Richards et al., 2015, PMID 25741868; criteria: PM2 PP3).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242457	SCV001415547	uncertain significance	Hereditary spastic paraplegia 49	2021-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 903 of the TECPR2 protein (p.Thr903Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs752912949, ExAC 0.02%). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 27406698). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779140	SCV002015087	uncertain significance	not specified	2021-10-27	criteria provided, single submitter	clinical testing	Variant summary: TECPR2 c.2708C>T (p.Thr903Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251228 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TECPR2 causing Hereditary Spastic Paraplegia, Type 49 (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.2708C>T has been reported in the literature an individual with clinical features of hereditary spastic paraplegia who carried the variant in the compound heterozygous state (Covone_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847206	SCV002105933	uncertain significance	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001242457	SCV002091132	uncertain significance	Hereditary spastic paraplegia 49	2020-11-04	no assertion criteria provided	clinical testing