VCV000458260.16 - ClinVar

NM_014363.6(SACS):c.2599T>C (p.Tyr867His)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance

3 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014363.6(SACS):c.2599T>C (p.Tyr867His)

Variation ID: 458260 Accession: VCV000458260.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q12.12 13: 23341277 (GRCh38) [ NCBI UCSC ] 13: 23915416 (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	Dec 26, 2017	Feb 7, 2023	Jul 19, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_014363.6:c.2599T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055178.3:p.Tyr867His	missense
NM_001278055.2:c.2158T>C	NP_001264984.1:p.Tyr720His	missense
NC_000013.11:g.23341277A>G
NC_000013.10:g.23915416A>G
NG_012342.1:g.97426T>C

... more HGVS ... less HGVS

Protein change

Y867H, Y720H

Other names

Canonical SPDI

NC_000013.11:23341276:A:G

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA6911660 dbSNP: rs774682589 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.
SACS		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	4772	4992

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.
Spastic paraplegia	Uncertain significance (1)	criteria provided, single submitter	Jul 19, 2022	RCV000560347.6
not provided	Uncertain significance (1)	criteria provided, single submitter	Feb 12, 2020	RCV001508705.5
Charlevoix-Saguenay spastic ataxia	Uncertain significance (2)	criteria provided, single submitter	Sep 5, 2021	RCV001783032.4

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.	Expand all rows Collapse all rows 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 (Jul 19, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Spastic paraplegia	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000629462.3 First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023	Comment: show This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 867 of the SACS protein (p.Tyr867His). This variant is present in population databases (rs774682589, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SACS-related conditions. ClinVar contains an entry for this variant (Variation ID: 458260). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Feb 12, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715031.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1

Uncertain significance (Sep 05, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Charlevoix-Saguenay spastic ataxia	Genome-Nilou Lab Accession: SCV002026537.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Uncertain significance (Mar 09, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Charlevoix-Saguenay type spastic ataxia	Natera, Inc. Accession: SCV002086714.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 867 of the SACS protein (p.Tyr867His). This variant is present in population databases (rs774682589, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SACS-related conditions. ClinVar contains an entry for this variant (Variation ID: 458260). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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 rs774682589 ...

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 May 17, 2025