The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family, however, the available information does not rule out an apparent association due to chance. 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. The variant is located in a region that is considered important for protein function and/or structure.
ClinVar Genomic variation as it relates to human health
NM_003119.4(SPG7):c.1948G>A (p.Asp650Asn)
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.
(7)
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.
Conflicting classifications of pathogenicity
Pathogenic(4); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(4); Likely pathogenic(2); Uncertain significance(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003119.4(SPG7):c.1948G>A (p.Asp650Asn)
Variation ID: 220101 Accession: VCV000220101.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q24.3 16: 89553805 (GRCh38) [ NCBI UCSC ] 16: 89620213 (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 Mar 3, 2018 Nov 24, 2024 Jan 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003119.4:c.1948G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003110.1:p.Asp650Asn missense NM_001363850.1:c.1948G>A NP_001350779.1:p.Asp650Asn missense NC_000016.10:g.89553805G>A NC_000016.9:g.89620213G>A NG_008082.1:g.50409G>A - Protein change
- D650N
- Other names
-
p.Asp650Asn
- Canonical SPDI
- NC_000016.10:89553804:G:A
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- 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. |
|||
| SPG7 | - | - |
GRCh38 GRCh37 |
979 | 1151 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 9, 2024 | RCV000205405.20 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 15, 2023 | RCV000585273.29 |
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
(Jan 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000844097.3
First in ClinVar: Mar 03, 2018 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family, however, the available information does not rule out an apparent association due to chance. 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. The variant is located in a region that is considered important for protein function and/or structure. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 7
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001522925.2
First in ClinVar: Mar 22, 2021 Last updated: Mar 18, 2023 |
|
|
|
Pathogenic
(Nov 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 7
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223526.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: SPG7 c.1948G>A (p.Asp650Asn) results in a conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Three … (more)
Variant summary: SPG7 c.1948G>A (p.Asp650Asn) results in a conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250772 control chromosomes (gnomAD). c.1948G>A has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia 7 and the variant co-segregated with the disease (Fogel_2014, Dela Casa-Fages_2019, Fernndez-Moreno_2020, Charif_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33841295, 31433872, 32204931, 25133958). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 7
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003810922.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 7
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000260385.10
First in ClinVar: Feb 02, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 650 of the SPG7 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 650 of the SPG7 protein (p.Asp650Asn). This variant is present in population databases (rs769602042, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 31433872, 32204931; Invitae). 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: 220101). 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 SPG7 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Uncertain significance
(Oct 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000692884.30
First in ClinVar: Mar 03, 2018 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413160.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP1_strong, PP3, PM1_supporting, PM3_supporting
Number of individuals with the variant: 1
|
Comment:
Comment:
Variant summary: SPG7 c.1948G>A (p.Asp650Asn) results in a conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250772 control chromosomes (gnomAD). c.1948G>A has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia 7 and the variant co-segregated with the disease (Fogel_2014, Dela Casa-Fages_2019, Fernndez-Moreno_2020, Charif_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33841295, 31433872, 32204931, 25133958). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 650 of the SPG7 protein (p.Asp650Asn). This variant is present in population databases (rs769602042, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 31433872, 32204931; Invitae). 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: 220101). 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 SPG7 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Comment:
PP1_strong, PP3, PM1_supporting, PM3_supporting
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:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family, however, the available information does not rule out an apparent association due to chance. 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. The variant is located in a region that is considered important for protein function and/or structure.
Comment:
Variant summary: SPG7 c.1948G>A (p.Asp650Asn) results in a conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250772 control chromosomes (gnomAD). c.1948G>A has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia 7 and the variant co-segregated with the disease (Fogel_2014, Dela Casa-Fages_2019, Fernndez-Moreno_2020, Charif_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33841295, 31433872, 32204931, 25133958). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 650 of the SPG7 protein (p.Asp650Asn). This variant is present in population databases (rs769602042, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 31433872, 32204931; Invitae). 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: 220101). 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 SPG7 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Comment:
PP1_strong, PP3, PM1_supporting, PM3_supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and genetic characteristics of 21 Spanish patients with biallelic pathogenic SPG7 mutations. | Baviera-Muñoz R | Journal of the neurological sciences | 2021 | PMID: 34500365 |
| Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy. | Charif M | Frontiers in neurology | 2021 | PMID: 33841295 |
| A Spanish family with a compound heterozygous mutation in SPG7: From uncertainty to clinical reality. | Fernández-Moreno MC | Neurologia | 2020 | PMID: 32204931 |
| Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism. | De la Casa-Fages B | Movement disorders : official journal of the Movement Disorder Society | 2019 | PMID: 31433872 |
| Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. | Fogel BL | JAMA neurology | 2014 | PMID: 25133958 |
Text-mined citations for rs769602042 ...
HelpThese 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 Nov 30, 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.