NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Dec 29, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001268887.19

Allele description [Variation Report for NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)]

NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)

Gene:

SPG11:SPG11 vesicle trafficking associated, spatacsin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)

HGVS:

NC_000015.10:g.44584299A>G
NG_008885.1:g.84380T>C
NM_001160227.2:c.5381T>C
NM_025137.4:c.5381T>CMANE SELECT
NP_001153699.1:p.Leu1794Pro
NP_079413.3:p.Leu1794Pro
NC_000015.9:g.44876497A>G
NM_025137.3:c.5381T>C

Protein change:

L1794P

Links:

dbSNP: rs201689565

NCBI 1000 Genomes Browser:

rs201689565

Molecular consequence:

NM_001160227.2:c.5381T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_025137.4:c.5381T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001448123	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001474775	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Likely pathogenic (Oct 19, 2020)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27790088, 26374131, 31407473, 26467025
SCV001795085	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 29, 2023)	germline	clinical testing	Citation Link,
SCV002064389	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 26, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003820048	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004026402	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rare Variants in Neurodegeneration Associated Genes Revealed by Targeted Panel Sequencing in a German ALS Cohort.

Krüger S, Battke F, Sprecher A, Munz M, Synofzik M, Schöls L, Gasser T, Grehl T, Prudlo J, Biskup S.

Front Mol Neurosci. 2016;9:92.

PubMed [citation]

PMID:: 27790088
PMCID:: PMC5061735

Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing.

Lynch DS, Koutsis G, Tucci A, Panas M, Baklou M, Breza M, Karadima G, Houlden H.

Eur J Hum Genet. 2016 Jun;24(6):857-63. doi: 10.1038/ejhg.2015.200. Epub 2015 Sep 16.

PubMed [citation]

PMID:: 26374131
PMCID:: PMC4688955

See all PubMed Citations (5)

Details of each submission

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001448123.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV001474775.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001795085.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27790088, 26374131, 31407473, 34426522, 31589614, 33098801, 35254204, 35872528, 36549973, 36139378, 35906604, 34983064)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002064389.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

DNA sequence analysis of the SPG11 gene demonstrated a c.5381T>C in exon 30, results in an amino acid change, p.Leu1794Pro. The p.Leu1794Pro change affects a highly conserved amino acid residue located in a domain of the SPG11 protein that is not known to be functional. The p.Leu1794Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been reported in the compound heterozygous state with a truncating variant in three unrelated families with spastic paraplegia (Lynch et al., 2016). This sequence change has been described in the gnomAD database with a global population frequency of 0.0057% (dbSNP rs201689565).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003820048.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV004026402.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PM3, PP4, PP3, PM2_SUP, PP1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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