Submissions for variant NM_014844.5(TECPR2):c.3416del (p.Leu1139fs)

gnomAD frequency: 0.00001  dbSNP: rs751970061

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000386910	SCV000329920	pathogenic	not provided	2022-09-01	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23176824, 32209221, 23439247, 33218264, 33847017, 26542466)
Counsyl	RCV000032879	SCV000799615	likely pathogenic	Hereditary spastic paraplegia 49	2018-05-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000032879	SCV000956495	pathogenic	Hereditary spastic paraplegia 49	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1139Argfs*75) 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 (rs751970061, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with complicated hereditary spastic paraplegia in Jewish Bukharian families or autonomic neuropathy with intellectual disability (PMID: 23176824, 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: 39675). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000032879	SCV001386476	pathogenic	Hereditary spastic paraplegia 49	2020-07-11	criteria provided, single submitter	curation	This variant has been reported in homozygous state in five individuals of three families from Jewish Bukharian descent (PMID: 23176824). Additionally, the variant was identified in another individual in compound heterozygous state (with c.1319del, p.(Leu440Argfs*19) from Ashkenazi Jewish-Tunisian / Yamani-Kurdish descent (PMID: 26542466). All affected individuals displayed developmental delay, muscular hypotonia and symptoms of autonomic neuropathy. This frameshift variant c.3416del, p.(Leu1139Argfs*75) in exon 16/20 of TECPR2 has a minor allel frequency in the general population of 0.000008082 (gnomAD). The variant is already reported in ClinVar as pathogenic/likely pathogenic (ID: 39675). 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	RCV000032879	SCV005637437	pathogenic	Hereditary spastic paraplegia 49	2024-02-05	criteria provided, single submitter	clinical testing
OMIM	RCV000032879	SCV000056649	pathogenic	Hereditary spastic paraplegia 49	2012-12-07	no assertion criteria provided	literature only
Natera, Inc.	RCV000032879	SCV001460239	pathogenic	Hereditary spastic paraplegia 49	2020-09-16	no assertion criteria provided	clinical testing