VCV001704567.6 - ClinVar

NM_014363.6(SACS):c.7163C>T (p.Thr2388Ile)

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.

(3)

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
Uncertain significance(2); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014363.6(SACS):c.7163C>T (p.Thr2388Ile)

Variation ID: 1704567 Accession: VCV001704567.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q12.12 13: 23336713 (GRCh38) [ NCBI UCSC ] 13: 23910852 (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	Sep 17, 2022	May 1, 2024	Jan 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014363.6:c.7163C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055178.3:p.Thr2388Ile	missense
NM_001278055.2:c.6722C>T	NP_001264984.1:p.Thr2241Ile	missense
NM_014363.4:c.7163C>T
NC_000013.11:g.23336713G>A
NC_000013.10:g.23910852G>A
NG_012342.1:g.101990C>T

... more HGVS ... less HGVS

Protein change

T2388I, T2241I

Other names

Canonical SPDI

NC_000013.11:23336712:G:A

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.

Links

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		-	-	GRCh38 GRCh37	4093	4295

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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Jul 12, 2022	RCV002282894.1
Spastic paraplegia	Likely benign (1)	criteria provided, single submitter	Jan 5, 2024	RCV003096343.3
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Apr 24, 2023	RCV003289498.2

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 (Jul 12, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002570859.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: Variant summary: SACS c.7163C>T (p.Thr2388Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign … (more) Variant summary: SACS c.7163C>T (p.Thr2388Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250606 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (6.8e-05 vs 0.0079), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7163C>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Likely benign (Jan 05, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Spastic paraplegia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003509683.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024
Uncertain significance (Apr 24, 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: SCV003956724.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The c.7163C>T (p.T2388I) alteration is located in exon 10 (coding exon 9) of the SACS gene. This alteration results from a C to T substitution … (more) The c.7163C>T (p.T2388I) alteration is located in exon 10 (coding exon 9) of the SACS gene. This alteration results from a C to T substitution at nucleotide position 7163, causing the threonine (T) at amino acid position 2388 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)

Comment:

Variant summary: SACS c.7163C>T (p.Thr2388Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250606 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (6.8e-05 vs 0.0079), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7163C>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

The c.7163C>T (p.T2388I) alteration is located in exon 10 (coding exon 9) of the SACS gene. This alteration results from a C to T substitution at nucleotide position 7163, causing the threonine (T) at amino acid position 2388 to be replaced by an isoleucine (I). 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 this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_014363.6(SACS):c.7163C>T (p.Thr2388Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...