VCV000648642.8 - ClinVar

NM_000159.4(GCDH):c.782C>T (p.Thr261Ile)

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.

(4)

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_000159.4(GCDH):c.782C>T (p.Thr261Ile)

Variation ID: 648642 Accession: VCV000648642.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.13 19: 12896351 (GRCh38) [ NCBI UCSC ] 19: 13007165 (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	Aug 14, 2019	Oct 20, 2024	Aug 27, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000159.4:c.782C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000150.1:p.Thr261Ile	missense
NM_013976.5:c.782C>T	NP_039663.1:p.Thr261Ile	missense
NR_102316.1:n.945C>T		non-coding transcript variant
NR_102317.1:n.1163C>T		non-coding transcript variant
NC_000019.10:g.12896351C>T
NC_000019.9:g.13007165C>T
NG_009292.1:g.10192C>T

... more HGVS ... less HGVS

Protein change

T261I

Other names

Canonical SPDI

NC_000019.10:12896350:C:T

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.

The Genome Aggregation Database (gnomAD) 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

dbSNP: rs777494547 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.
GCDH		-	-	GRCh38 GRCh37	685	911

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.
Glutaric aciduria, type 1	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Aug 27, 2021	RCV000803410.9

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 (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Glutaric aciduria, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001286370.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Aug 27, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glutaric aciduria, type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000943280.2 First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023	Comment: This sequence change replaces threonine with isoleucine at codon 261 of the GCDH protein (p.Thr261Ile). The threonine residue is highly conserved and there is a … (more) This sequence change replaces threonine with isoleucine at codon 261 of the GCDH protein (p.Thr261Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs777494547, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with GCDH-related conditions. 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 disruptive. 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)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glutaric aciduria, type 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005374774.1 First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024	Comment: The observed missense variant c.4265A>C (p.Gln1422Pro) in KIF26B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our … (more) The observed missense variant c.4265A>C (p.Gln1422Pro) in KIF26B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gln1422Pro variant is absent on gnomAD Exomes database. This variant has not been submitted to the ClinVar database. The reference amino acid at this position on KIF26B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (SIFT - tolerated; Polyphen - benign; MutationTaster - polymorphism) predict no effect on protein structure and function for this variant. The amino acid Gln at position 1422 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). (less)
Uncertain significance (Mar 11, 2020)	no assertion criteria provided Method: clinical testing	Glutaric acidemia type 1 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001455954.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces threonine with isoleucine at codon 261 of the GCDH protein (p.Thr261Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs777494547, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with GCDH-related conditions. 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 disruptive. 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.

Comment:

The observed missense variant c.4265A>C (p.Gln1422Pro) in KIF26B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gln1422Pro variant is absent on gnomAD Exomes database. This variant has not been submitted to the ClinVar database. The reference amino acid at this position on KIF26B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (SIFT - tolerated; Polyphen - benign; MutationTaster - polymorphism) predict no effect on protein structure and function for this variant. The amino acid Gln at position 1422 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

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 rs777494547 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000159.4(GCDH):c.782C>T (p.Thr261Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777494547 ...