Submissions for variant NM_014844.5(TECPR2):c.1319del (p.Leu440fs)

gnomAD frequency: 0.00008  dbSNP: rs750908377

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000414835	SCV000965238	pathogenic	Hereditary spastic paraplegia 49	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu440Argfs*19) in the TECPR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TECPR2 are known to be pathogenic (PMID: 23176824, 25590979). This variant is present in population databases (rs750908377, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with autonomic dysfunction and intellectual disability (PMID: 25590979, 26542466). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374308). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001008810	SCV001168611	pathogenic	not provided	2022-04-14	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33847017, 27959697, 26542466, 25590979, 32209221, 33884296)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000414835	SCV001423562	pathogenic	Hereditary spastic paraplegia 49	2020-06-27	criteria provided, single submitter	research	This homozygous variant was identified by (trio-)exome sequencing in three individuals (9 month old female, 2 year old male and 3 year old male) with developmental delay and muscular hypotonia. The families are from Ashkenazi Jewish descent. Each parents are heterozygous carriers for this variant. This frameshift variant c.1319del, p.(Leu440Argfs*19) in exon 8/20 of TECPR2 has a minor allel frequency in the general population of 0.0001342 (gnomAD). Two publications (PMID: 25590979, 26542466) report four similarly affected patients with this variant (homozygous or compound heterozygous). The variant is already reported in ClinVar as pathogenic (ID: 374308). 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). Taken together, we classify this variant as pathogenic based on the ACMG recommendations (Richards et al., 2015, PMID 25741868; criteria: PVS1 PS4_MOD PM2).
Fulgent Genetics, Fulgent Genetics	RCV000414835	SCV002815506	pathogenic	Hereditary spastic paraplegia 49	2024-03-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000414835	SCV003828007	pathogenic	Hereditary spastic paraplegia 49	2022-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330660	SCV004038215	pathogenic	Hereditary spastic paraplegia	2023-08-02	criteria provided, single submitter	clinical testing	Variant summary: TECPR2 c.1319delT (p.Leu440ArgfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 244296 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TECPR2 causing Hereditary Spastic Paraplegia, Type 49 (0.00015 vs 0.0011), allowing no conclusion about variant significance. c.1319delT has been reported in the literature as a biallelic genotype in multiple individuals affected with Hereditary Spastic Paraplegia, Type 49 (e.g. Zhu_2015, Heimer_2016, Neuser_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26542466, 33847017, 25590979). Eight ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000414835	SCV000328784	pathogenic	Hereditary spastic paraplegia 49	2015-11-12	no assertion criteria provided	clinical testing	Our laboratory reported three molecular diagnoses in DFNA5 (NM_004403.2, c.119dup), FLG (NM_002016.1, c.4279G>A), and TECPR2 (NM_014844.3, c.1319del) in one individual with reported features which include delayed motor milestones, delayed speech, developmental regression, mild bilateral sensorineural hearing loss, hypotonia, hyporeflexia, dysmorphic features, short stature, hyperextensibility, ichthyosis, hypothyroidism, mild elevation of CK and eye anomalies. The c.1319del (p.L440fs) TECPR2 change has been reported in three unrelated Ashkenazi Jewish patients of non-Bukharian origin [PMID 26542466], either homozygous or compound heterozygous, leading to hereditary sensory-autonomic neuropathy. Heterozygotes are expected to be asymptomatic carriers.
OMIM	RCV000414835	SCV001890895	pathogenic	Hereditary spastic paraplegia 49	2021-10-19	no assertion criteria provided	literature only
Natera, Inc.	RCV000414835	SCV002088006	pathogenic	Hereditary spastic paraplegia 49	2017-09-24	no assertion criteria provided	clinical testing