NM_014946.4(SPAST):c.1245+5G>A AND Hereditary spastic paraplegia 4

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 6, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001729680.10

Allele description [Variation Report for NM_014946.4(SPAST):c.1245+5G>A]

NM_014946.4(SPAST):c.1245+5G>A

Gene:

SPAST:spastin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.3

Genomic location:

Preferred name:

NM_014946.4(SPAST):c.1245+5G>A

HGVS:

NC_000002.12:g.32128484G>A
NG_008730.1:g.69874G>A
NM_001363823.2:c.1242+5G>A
NM_001363875.2:c.1146+5G>A
NM_001377959.1:c.1149+5G>A
NM_014946.4:c.1245+5G>AMANE SELECT
NM_199436.2:c.1149+5G>A
LRG_714t1:c.1245+5G>A
LRG_714:g.69874G>A
NC_000002.11:g.32353553G>A
NM_014946.3:c.1245+5G>A

Links:

dbSNP: rs1553317049

NCBI 1000 Genomes Browser:

rs1553317049

Molecular consequence:

NM_001363823.2:c.1242+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001363875.2:c.1146+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001377959.1:c.1149+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_014946.4:c.1245+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_199436.2:c.1149+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hereditary spastic paraplegia 4
Synonyms:: Spastic paraplegia 4, autosomal dominant; Familial spastic paraplegia autosomal dominant 2
Identifiers:: MONDO: MONDO:0008438; MedGen: C1866855; Orphanet: 100985; OMIM: 182601

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001976987	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 1, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34008892, 25741868
SCV002316669	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 6, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22552817, 30476002, 34008892, 17576681, 9536098, 33638609, 28492532
SCV002557460	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2020)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11309678, 22552817, 24478365, 24648003, 27260292, 28572275, 30006150, 30476002, 30520996, 25741868
SCV005091381	Solve-RD Consortium	no assertion criteria provided	Likely pathogenic (Jun 1, 2022)	inherited	provider interpretation

Help

Summary from all submissions

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

Citations

PubMed

Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.

Marinakis NM, Svingou M, Veltra D, Kekou K, Sofocleous C, Tilemis FN, Kosma K, Tsoutsou E, Fryssira H, Traeger-Synodinos J.

Am J Med Genet A. 2021 Aug;185(8):2561-2571. doi: 10.1002/ajmg.a.62338. Epub 2021 May 19.

PubMed [citation]

PMID:: 34008892

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (15)

Details of each submission

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976987.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

PM1, PM2, PP3, PP4, PP5

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002316669.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

ClinVar contains an entry for this variant (Variation ID: 546862). This sequence change falls in intron 9 of the SPAST gene. It does not directly change the encoded amino acid sequence of the SPAST protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 22552817, 30476002, 33638609, 34008892; Invitae). It has also been observed to segregate with disease in related individuals. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 33638609). For these reasons, this variant has been classified as Pathogenic.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557460.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Multiple premature termination codon variants resulting in loss of function have been reported whilst a missense variant has been shown to have gain of function effects (ClinVar; PMID 24478365; PMID 30520996). (N) 0104 - Dominant Negative is a mechanism of disease for this gene for other missense variants (PMID 30006150). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID 30476002). (N) 0212 - Non-canonical splice variant without proven consequence on splicing (no functional evidence available) (intron 9 of 16). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple non-canonical splice variants within the same donor region have previously been reported in clinical cases (ClinVar; PMID 22552817; PMID 24648003; PMID 11309678). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in association with hereditary spastic paraplegia (ClinVar; PMID 27260292; PMID 22552817; PMID 28572275). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	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 Solve-RD Consortium, SCV005091381.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

Variant confirmed as disease-causing by referring clinical team

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

Last Updated: Oct 26, 2024

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