VCV000039675.17 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

5 out of 7 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 39675 Accession: VCV000039675.17

Type and length

Deletion, 1 bp

Location

Cytogenetic: 14q32.31 14: 102452403 (GRCh38) [ NCBI UCSC ] 14: 102918740 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 30, 2013	Apr 13, 2025	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014844.5:c.3416del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055659.2:p.Leu1139fs	frameshift
NM_014844.5:c.3416delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001172631.3:c.3416del	NP_001166102.1:p.Leu1139fs	frameshift
NM_014844.3:c.3416delT
NC_000014.9:g.102452403del
NC_000014.8:g.102918740del
NG_042851.1:g.94492del

... more HGVS ... less HGVS

Protein change

L1139fs

Other names

Canonical SPDI

NC_000014.9:102452402:T:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

protein truncation; Variation Ontology [VariO:0015]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA7358240 OMIM: 615000.0001 dbSNP: rs751970061 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TECPR2		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1401	1489

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary spastic paraplegia 49	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000032879.16
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 1, 2022	RCV000386910.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329920.8 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Likely pathogenic (May 03, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Hereditary spastic paraplegia 49 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000799615.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (3) PubMed: 26431026‚ 23176824‚ 26542466
Pathogenic (Dec 19, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 49 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000956495.5 First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 23176824‚ 25590979‚ 26542466 Comment: This sequence change creates a premature translational stop signal (p.Leu1139Argfs75) in the TECPR2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu1139Argfs75) 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. (less)
Pathogenic (Jul 11, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hereditary spastic paraplegia 49 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001386476.2 First in ClinVar: Aug 02, 2020 Last updated: Apr 13, 2025	Comment: 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 … (more) 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.(Leu440Argfs19) 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.(Leu1139Argfs75) 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). (less) Number of individuals with the variant: 6 Zygosity: Homozygote, Compound Heterozygote Sex: mixed Ethnicity/Population group: Jewish Bukharian, Ashkenazi Jewish-Tunisian / Yamani-Kurdish Geographic origin: Israel
Pathogenic (Feb 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 49 Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005637437.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Pathogenic (Dec 07, 2012) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IX, WITH DEVELOPMENTAL DELAY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000056649.5 First in ClinVar: Apr 04, 2013 Last updated: Oct 25, 2021	Publications: PubMed (3) PubMed: 23176824‚ 26542466‚ 33847017 Comment on evidence: In affected members of 3 Jewish Bukharian families with hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9; 615031), who were originally diagnosed … (more) In affected members of 3 Jewish Bukharian families with hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9; 615031), who were originally diagnosed with autosomal recessive spastic paraplegia-49 (SPG49), Oz-Levi et al. (2012) identified a homozygous 1-bp deletion (c.3416delT) in exon 16 of the TECPR2 gene, resulting in a frameshift and premature termination (Leu1139ArgfsTer75). The mutation was found by exome sequencing and segregated with the disorder in each family. The mutation was not present in 2,007 non-Bukharian controls, but was found in 4 of 300 Jewish Bukharian control chromosomes, yielding an allele frequency of 0.013 in that ethnic group. In vitro cellular expression assays indicated that the mutant protein was degraded by the proteosome. In a patient with HSAN9 (patient 3), Heimer et al. (2016) identified compound heterozygosity for 2 mutations in the TECPR2 gene: c.3416delT (c.3416delT, NM_001172631) and a 1-bp deletion (c.1319delT; 615000.0002) in exon 8, predicted to result in a frameshift and premature termination (Leu440ArgfsTer19). The mutations were identified by Sanger sequencing of the TECPR2 gene, and both parents were shown to be mutation carriers. In 2 patients with HSAN9, Neuser et al. (2021) identified homozygosity for the c.3416delT mutation in the TECPR2 gene. They noted that the minor allele frequency of the c.3416delT variant was 2/247,472 in only heterozygous state in the gnomAD database. (less)
Pathogenic (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Autosomal recessive spastic paraplegia type 49 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460239.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

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)

Comment:

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.

Comment:

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).

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
protein truncation (VariO:0015)			Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001386476.2

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.	Neuser S	Human mutation	2021	PMID: 33847017
TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability.	Heimer G	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2016	PMID: 26542466
TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export.	Stadel D	Molecular cell	2015	PMID: 26431026
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.	Zhu X	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25590979
Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis.	Oz-Levi D	American journal of human genetics	2012	PMID: 23176824

Text-mined citations for rs751970061 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2025

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs751970061 ...