VCV000212291.12 - ClinVar

NM_014946.4(SPAST):c.1813A>G (p.Ile605Val)

Germline

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014946.4(SPAST):c.1813A>G (p.Ile605Val)

Variation ID: 212291 Accession: VCV000212291.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p22.3 2: 32154458 (GRCh38) [ NCBI UCSC ] 2: 32379527 (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	Oct 5, 2015	Nov 24, 2024	Aug 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014946.4:c.1813A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055761.2:p.Ile605Val	missense
NM_001363823.2:c.1810A>G	NP_001350752.1:p.Ile604Val	missense
NM_001363875.2:c.1714A>G	NP_001350804.1:p.Ile572Val	missense
NM_001377959.1:c.*86A>G		3 prime UTR
NM_199436.2:c.1717A>G	NP_955468.1:p.Ile573Val	missense
NC_000002.12:g.32154458A>G
NC_000002.11:g.32379527A>G
NG_008730.1:g.95848A>G
LRG_714:g.95848A>G
LRG_714t1:c.1813A>G	LRG_714p1:p.Ile605Val

... more HGVS ... less HGVS

Protein change

I605V, I604V, I572V, I573V

Other names

p.Ile605Val

Canonical SPDI

NC_000002.12:32154457:A:G

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

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

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA208917 dbSNP: rs372900676 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.
SPAST		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1335	1402

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 4	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 17, 2022	RCV000199776.7
not specified	Uncertain significance (1)	criteria provided, single submitter	Jun 27, 2014	RCV000194626.6
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Sep 20, 2023	RCV004020343.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 22, 2024	RCV004791317.1

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.
Uncertain significance (Jun 27, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000249013.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Uncertain significance (May 19, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Hereditary spastic paraplegia 4 Affected status: unknown Allele origin: inherited	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001622867.1 First in ClinVar: May 21, 2021 Last updated: May 21, 2021	Clinical Features: Autistic behavior (present) , Attention deficit hyperactivity disorder (present) , Epistaxis (present) , Cryptorchidism (present) , Generalized hypotonia (present) , Macrocephaly (present) , Babinski sign … (more) Autistic behavior (present) , Attention deficit hyperactivity disorder (present) , Epistaxis (present) , Cryptorchidism (present) , Generalized hypotonia (present) , Macrocephaly (present) , Babinski sign (present) , Global developmental delay (present) (less) Secondary finding: no
Uncertain significance (Mar 17, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000255009.5 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 605 of the SPAST protein (p.Ile605Val). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 605 of the SPAST protein (p.Ile605Val). This variant is present in population databases (rs372900676, gnomAD 0.002%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 212291). This variant has not been reported in the literature in individuals affected with SPAST-related conditions. (less)
Uncertain significance (Sep 20, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004957375.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The c.1813A>G (p.I605V) alteration is located in exon 17 (coding exon 17) of the SPAST gene. This alteration results from a A to G substitution … (more) The c.1813A>G (p.I605V) alteration is located in exon 17 (coding exon 17) of the SPAST gene. This alteration results from a A to G substitution at nucleotide position 1813, causing the isoleucine (I) at amino acid position 605 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Aug 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005411664.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Number of individuals with the variant: 1

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 605 of the SPAST protein (p.Ile605Val). This variant is present in population databases (rs372900676, gnomAD 0.002%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 212291). This variant has not been reported in the literature in individuals affected with SPAST-related conditions.

Comment:

The c.1813A>G (p.I605V) alteration is located in exon 17 (coding exon 17) of the SPAST gene. This alteration results from a A to G substitution at nucleotide position 1813, causing the isoleucine (I) at amino acid position 605 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs372900676 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_014946.4(SPAST):c.1813A>G (p.Ile605Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs372900676 ...