This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein (p.Arg239Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 14607301, 15517445, 19652243, 25637064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATL1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 20816793, 23079343). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_015915.5(ATL1):c.715C>T (p.Arg239Cys)
Germline
Classification
Help
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.
(21)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
21
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_015915.5(ATL1):c.715C>T (p.Arg239Cys)
Variation ID: 4346 Accession: VCV000004346.79
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q22.1 14: 50613343 (GRCh38) [ NCBI UCSC ] 14: 51080061 (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 Apr 4, 2013 Oct 26, 2024 Apr 23, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015915.5:c.715C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056999.2:p.Arg239Cys missense NM_001127713.1:c.715C>T NP_001121185.1:p.Arg239Cys missense NM_181598.4:c.715C>T NP_853629.2:p.Arg239Cys missense NC_000014.9:g.50613343C>T NC_000014.8:g.51080061C>T NG_009028.1:g.85262C>T LRG_360:g.85262C>T LRG_360t1:c.715C>T LRG_360p1:p.Arg239Cys LRG_360t2:c.715C>T LRG_360p2:p.Arg239Cys Q8WXF7:p.Arg239Cys - Protein change
- R239C
- Other names
-
NM_001127713.1(ATL1):c.715C>T(p.Arg239Cys)
NM_015915.4(ATL1):c.715C>T(p.Arg239Cys)
NM_181598.3(ATL1):c.715C>T(p.Arg239Cys)
- Canonical SPDI
- NC_000014.9:50613342:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ATL1 | - | - |
GRCh38 GRCh37 |
559 | 596 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Apr 23, 2024 | RCV000004594.36 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2022 | RCV000215830.34 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Dec 31, 2017 | RCV000850530.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001003978.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 1, 2018 | RCV001847579.10 |
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
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446549.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Spastic paraplegia (present)
Sex: female
|
|
|
Likely pathogenic
(Aug 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 3A
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581735.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PP1_STR, PS4_MOD, PS3_SUP, PM2_SUP
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Pathogenic
(Dec 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 3A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764765.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Gait disturbance (present) , Hyperreflexia (present) , Spastic paraplegia (present) , Neck muscle weakness (present)
|
|
|
Pathogenic
(Jan 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 3A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000259322.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein (p.Arg239Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 14607301, 15517445, 19652243, 25637064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATL1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 20816793, 23079343). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Hereditary spastic paraplegia 3A
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803456.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
Comment:
This variant is interpreted as a Pathogenic, for Spastic paraplegia 3, autosomal dominant, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1-Strong => … (more)
This variant is interpreted as a Pathogenic, for Spastic paraplegia 3, autosomal dominant, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1-Strong => PP1 upgraded in strength to Strong (PMID:14607301) (PMID:11685207). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation in independent families (PMID:20932283,11685207,20718791,14607301). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:17321752). (less)
|
|
|
Pathogenic
(Dec 31, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000612432.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
|
|
|
Pathogenic
(Dec 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary sensory, type 1D
Hereditary spastic paraplegia 3A
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000992739.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
|
|
|
Pathogenic
(Dec 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 3A
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362053.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ATL1 c.715C>T (p.Arg239Cys) results in a non-conservative amino acid change located in the Guanylate-binding domain, N-terminal (IPR015894) of the encoded protein sequence. Three … (more)
Variant summary: ATL1 c.715C>T (p.Arg239Cys) results in a non-conservative amino acid change located in the Guanylate-binding domain, N-terminal (IPR015894) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes. c.715C>T has been reported in the literature in multiple individuals affected with Spastic paraplegia 3 (Zhao_2001, Novarino_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as evidenced by a disruption in BMPRII trafficking to the cell surface cell surface (example, Zhao_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 3A
Affected status: yes
Allele origin:
unknown
|
Paris Brain Institute, Inserm - ICM
Accession: SCV001451208.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 6
|
|
|
Pathogenic
(Jun 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002106241.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
|
|
|
Likely pathogenic
(Jan 25, 2022)
|
criteria provided, single submitter
Method: research
|
Hereditary spastic paraplegia 3A
Affected status: unknown
Allele origin:
unknown
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: CSER_NCGENES_2
Accession: SCV002587026.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022
Comment:
ATL1 c.715C>T p.(Arg239Cys) is predicted to change a single amino acid in the encoded protein from arginine to cysteine. This recurrent variant has been previously … (more)
ATL1 c.715C>T p.(Arg239Cys) is predicted to change a single amino acid in the encoded protein from arginine to cysteine. This recurrent variant has been previously reported in multiple individuals with uncomplicated spastic paraplegia (PMIDs 28396731, 20947813, 20932283, 20718791, 11685207, 14607301, 25637064, 26671083, 27084228, 27260292), and was observed to segregate with disease in affected family members (PMID 20947813, 20932283, 20718791). At least one case of de novo occurrence of this variant in an affected individual has been reported in the literature (PMID 25637064). This variant is absent from gnomAD. Functional evidence suggests this variant alters trafficking, localization and GTPase activity of the atlastin-1 protein, which results in disruption of the bone morphogenic protein-linked signaliing pathway in neurons (16537571, 17321752, 20816793, 23079343). This variant is classified as likely pathogenic. (less)
|
Number of individuals with the variant: 1
Clinical Features:
Hypospadias (present) , Hypertelorism (present) , Facial asymmetry (present) , Preauricular skin tag (present) , Mixed hearing impairment (present) , Telecanthus (present) , Autism (present) … (more)
Hypospadias (present) , Hypertelorism (present) , Facial asymmetry (present) , Preauricular skin tag (present) , Mixed hearing impairment (present) , Telecanthus (present) , Autism (present) , Intellectual disability, mild (present) , Spasticity (present) , Lower limb spasticity (present) , Spastic paraparesis (present) , Craniofacial asymmetry (present) , Aplasia/Hypoplasia of the external ear (present) , Hemifacial hypoplasia (present) (less)
|
|
|
Pathogenic
(Jan 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000279438.10
First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies indicate that R239C causes protein sequestration in the Golgi complex (Botzolakis et al., 2011); Not observed in large population cohorts (gnomAD); In … (more)
Published functional studies indicate that R239C causes protein sequestration in the Golgi complex (Botzolakis et al., 2011); Not observed 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: 15517445, 30778698, 19652243, 11685207, 23079343, 20947813, 20718791, 27260292, 27084228, 20816793, 25761634, 14607301, 31630374, 32277485, 32581362, 31216405, 34015694, 21194679, 23334294) (less)
|
|
|
Pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: research
|
Hereditary spastic paraplegia 3A
Affected status: yes
Allele origin:
germline
|
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920831.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
|
Pathogenic
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 3A
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812317.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
P1: HP:0001258, P2: HP:0001258 This sequence change in ATL1 is predicted to replace arginine with cysteine at codon 239, p.(Arg239Cys). The arginine residue is highly … (more)
P1: HP:0001258, P2: HP:0001258 This sequence change in ATL1 is predicted to replace arginine with cysteine at codon 239, p.(Arg239Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the GB1/RHD3-type G domain. There is a large physicochemical difference between arginine and cysteine. This variant is absent from gnomAD v2.1 and v3.1. This is a recurrent variant that has been reported in at least 15 probands/families with pure hereditary spastic paraplegia, and segregates with disease in multiple families (PMID: 15517445, 16612642, 19652243, 20718791, 20932283, 20947813, 25637064). Functional assays in heterologous systems showed impaired GTPase activity, and altered endoplasmic reticulum and Golgi morphology indicating that this variant impacts protein function (PMID: 16537571, 17321752). Computational evidence is uninformative for the missense substitution (REVEL=0.5). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting. (less)
|
|
|
Pathogenic
(Apr 23, 2024)
|
criteria provided, single submitter
Method: research
|
Hereditary spastic paraplegia 3A
(Sporadic)
Affected status: yes
Allele origin:
unknown
|
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)
Accession: SCV004933975.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein (p.Arg239Cys). This variant is predicted to be disease-causing by standard in silico prediction tools (CADD, SIFT, PolyPhen-2, and MutationTaster). ClinVar contains an entry for this variant (Variation ID: 4346), it’s classified as pathogenic/Likely Pathogenic. This variant is not reported in publicly available databases (1000 Genomes and gnomAD). This is a recurrent variant that has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 14607301, 15517445, 16612642, 19652243, 20718791, 20932283, 20947813, 25637064). Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 17321752, 20816793, 23079343). (less)
Clinical Features:
Spastic paraplegia (present) , Scoliosis (present) , Pes planus (present)
Age: 0-9 years
Sex: male
Geographic origin: Algeria
Comment on evidence:
This variant was absent in the patient’s unaffected parents, raising the possibility of either non-paternity or a de novo mutational event. We did not perform … (more)
This variant was absent in the patient’s unaffected parents, raising the possibility of either non-paternity or a de novo mutational event. We did not perform a paternity test, both possibilities remain conceivable. (less)
Testing laboratory: WES data were generated at the IGenSeq platform of the ICM Institute (Paris, France)
|
|
|
Pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001149210.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 4
|
|
|
Pathogenic
(May 01, 2006)
|
no assertion criteria provided
Method: literature only
|
SPASTIC PARAPLEGIA 3, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024768.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of 3 apparently unrelated kindreds with spastic paraplegia-3 (182600), Zhao et al. (2001) identified a heterozygous 884C-T transition in exon 7 of … (more)
In affected members of 3 apparently unrelated kindreds with spastic paraplegia-3 (182600), Zhao et al. (2001) identified a heterozygous 884C-T transition in exon 7 of the ATL1 gene, resulting in an arg239-to-cys (R239C) substitution. Abel et al. (2004) identified the R239C mutation in all 22 affected members of a French family with SPG3 reported by Hazan et al. (1993). Abel et al. (2004) stated that this was the seventh SPG3 family of western European descent found to have the R239C mutation. Abel et al. (2004) reported the nucleotide change as 715C-T, based on numbering from the translation initiation codon, and noted that position 715 is within a CpG doublet, suggesting that it is a possible mutation hotspot. By haplotype analysis of 3 French families with the R239C mutation, Namekawa et al. (2006) concluded that the mutations arose independently and were not due to a founder effect. Further analysis confirmed that the mutation occurred in a hotspot defined by a methylated CpG dinucleotide. (less)
|
|
|
Pathogenic
(Jan 29, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary spastic paraplegia 3A
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132816.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Spastic paraplegia
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162004.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Number of individuals with the variant: 1
Sex: male
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Hereditary spastic paraplegia 3A
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000041295.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Hereditary spastic paraplegia 3A
Neuropathy, hereditary sensory, type 1D
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228572.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Pathogenic and reported on 06-19-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 06-19-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Neurodevelopmental delay (present)
Indication for testing: Diagnostic, Family Testing
Age: 30-39 years
Sex: male
Method: Single Gene Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-06-19
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
This variant is interpreted as a Pathogenic, for Spastic paraplegia 3, autosomal dominant, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1-Strong => PP1 upgraded in strength to Strong (PMID:14607301) (PMID:11685207). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation in independent families (PMID:20932283,11685207,20718791,14607301). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:17321752).
Comment:
Variant summary: ATL1 c.715C>T (p.Arg239Cys) results in a non-conservative amino acid change located in the Guanylate-binding domain, N-terminal (IPR015894) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes. c.715C>T has been reported in the literature in multiple individuals affected with Spastic paraplegia 3 (Zhao_2001, Novarino_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as evidenced by a disruption in BMPRII trafficking to the cell surface cell surface (example, Zhao_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies indicate that R239C causes protein sequestration in the Golgi complex (Botzolakis et al., 2011); Not observed 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: 15517445, 30778698, 19652243, 11685207, 23079343, 20947813, 20718791, 27260292, 27084228, 20816793, 25761634, 14607301, 31630374, 32277485, 32581362, 31216405, 34015694, 21194679, 23334294)
Comment:
P1: HP:0001258, P2: HP:0001258 This sequence change in ATL1 is predicted to replace arginine with cysteine at codon 239, p.(Arg239Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the GB1/RHD3-type G domain. There is a large physicochemical difference between arginine and cysteine. This variant is absent from gnomAD v2.1 and v3.1. This is a recurrent variant that has been reported in at least 15 probands/families with pure hereditary spastic paraplegia, and segregates with disease in multiple families (PMID: 15517445, 16612642, 19652243, 20718791, 20932283, 20947813, 25637064). Functional assays in heterologous systems showed impaired GTPase activity, and altered endoplasmic reticulum and Golgi morphology indicating that this variant impacts protein function (PMID: 16537571, 17321752). Computational evidence is uninformative for the missense substitution (REVEL=0.5). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein (p.Arg239Cys). This variant is predicted to be disease-causing by standard in silico prediction tools (CADD, SIFT, PolyPhen-2, and MutationTaster). ClinVar contains an entry for this variant (Variation ID: 4346), it’s classified as pathogenic/Likely Pathogenic. This variant is not reported in publicly available databases (1000 Genomes and gnomAD). This is a recurrent variant that has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 14607301, 15517445, 16612642, 19652243, 20718791, 20932283, 20947813, 25637064). Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 17321752, 20816793, 23079343).
Comment:
Variant interpreted as Pathogenic and reported on 06-19-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein (p.Arg239Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 14607301, 15517445, 19652243, 25637064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATL1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 20816793, 23079343). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is interpreted as a Pathogenic, for Spastic paraplegia 3, autosomal dominant, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1-Strong => PP1 upgraded in strength to Strong (PMID:14607301) (PMID:11685207). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation in independent families (PMID:20932283,11685207,20718791,14607301). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:17321752).
Comment:
Variant summary: ATL1 c.715C>T (p.Arg239Cys) results in a non-conservative amino acid change located in the Guanylate-binding domain, N-terminal (IPR015894) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes. c.715C>T has been reported in the literature in multiple individuals affected with Spastic paraplegia 3 (Zhao_2001, Novarino_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as evidenced by a disruption in BMPRII trafficking to the cell surface cell surface (example, Zhao_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies indicate that R239C causes protein sequestration in the Golgi complex (Botzolakis et al., 2011); Not observed 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: 15517445, 30778698, 19652243, 11685207, 23079343, 20947813, 20718791, 27260292, 27084228, 20816793, 25761634, 14607301, 31630374, 32277485, 32581362, 31216405, 34015694, 21194679, 23334294)
Comment:
P1: HP:0001258, P2: HP:0001258 This sequence change in ATL1 is predicted to replace arginine with cysteine at codon 239, p.(Arg239Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the GB1/RHD3-type G domain. There is a large physicochemical difference between arginine and cysteine. This variant is absent from gnomAD v2.1 and v3.1. This is a recurrent variant that has been reported in at least 15 probands/families with pure hereditary spastic paraplegia, and segregates with disease in multiple families (PMID: 15517445, 16612642, 19652243, 20718791, 20932283, 20947813, 25637064). Functional assays in heterologous systems showed impaired GTPase activity, and altered endoplasmic reticulum and Golgi morphology indicating that this variant impacts protein function (PMID: 16537571, 17321752). Computational evidence is uninformative for the missense substitution (REVEL=0.5). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein (p.Arg239Cys). This variant is predicted to be disease-causing by standard in silico prediction tools (CADD, SIFT, PolyPhen-2, and MutationTaster). ClinVar contains an entry for this variant (Variation ID: 4346), it’s classified as pathogenic/Likely Pathogenic. This variant is not reported in publicly available databases (1000 Genomes and gnomAD). This is a recurrent variant that has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 14607301, 15517445, 16612642, 19652243, 20718791, 20932283, 20947813, 25637064). Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 17321752, 20816793, 23079343).
Comment:
Variant interpreted as Pathogenic and reported on 06-19-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Spastic Paraplegia 3A. | Adam MP | - | 2020 | PMID: 20862796 |
| ER network formation and membrane fusion by atlastin1/SPG3A disease variants. | Ulengin I | Molecular biology of the cell | 2015 | PMID: 25761634 |
| De novo mutations in SPG3A: a challenge in differential diagnosis and genetic counselling. | Leonardi L | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2015 | PMID: 25637064 |
| Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. | Novarino G | Science (New York, N.Y.) | 2014 | PMID: 24482476 |
| SPG3A-linked hereditary spastic paraplegia associated with cerebral glucose hypometabolism. | Terada T | Annals of nuclear medicine | 2013 | PMID: 23233086 |
| Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking. | Zhao J | Molecular and cellular neurosciences | 2013 | PMID: 23079343 |
| The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1. | Botzolakis EJ | Molecular and cellular neurosciences | 2011 | PMID: 20816793 |
| Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia. | McCorquodale DS 3rd | Clinical genetics | 2011 | PMID: 20718791 |
| Clinical and genetic analysis of a Korean family with hereditary spastic paraplegia type 3. | Kwon MJ | Annals of clinical and laboratory science | 2010 | PMID: 20947813 |
| Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. | Alvarez V | BMC neurology | 2010 | PMID: 20932283 |
| Hereditary spastic paraplegia: identification of an SPG3A gene mutation in a Chinese family. | Chan KY | Hong Kong medical journal = Xianggang yi xue za zhi | 2009 | PMID: 19652243 |
| Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis. | Namekawa M | Molecular and cellular neurosciences | 2007 | PMID: 17321752 |
| A founder effect and mutational hot spots may contribute to the most frequent mutations in the SPG3A gene. | Namekawa M | Neurogenetics | 2006 | PMID: 16612642 |
| SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. | Zhu PP | Human molecular genetics | 2006 | PMID: 16537571 |
| Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A. | Abel A | Neurogenetics | 2004 | PMID: 15517445 |
| SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia. | Wilkinson PA | Journal of the neurological sciences | 2003 | PMID: 14607301 |
| Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. | Zhao X | Nature genetics | 2001 | PMID: 11685207 |
| Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q. | Hazan J | Nature genetics | 1993 | PMID: 8252041 |
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Text-mined citations for rs119476046 ...
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Record last updated Oct 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.