ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs751970061
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Total submissions: 6
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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
Invitae 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).
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

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