VCV000440324.53 - ClinVar

NM_000355.4(TCN2):c.280G>A (p.Gly94Ser)

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.

(10)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000355.4(TCN2):c.280G>A (p.Gly94Ser)

Variation ID: 440324 Accession: VCV000440324.53

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.2 22: 30612895 (GRCh38) [ NCBI UCSC ] 22: 31008882 (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	Apr 20, 2018	Oct 20, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000355.4:c.280G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000346.2:p.Gly94Ser	missense
NM_001184726.2:c.280G>A	NP_001171655.1:p.Gly94Ser	missense
NC_000022.11:g.30612895G>A
NC_000022.10:g.31008882G>A
NG_007263.1:g.10722G>A
LRG_116:g.10722G>A

... more HGVS ... less HGVS

Protein change

G94S

Other names

Canonical SPDI

NC_000022.11:30612894: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.

0.00160 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00141

1000 Genomes Project 0.00160

The Genome Aggregation Database (gnomAD) 0.00162

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00177

Exome Aggregation Consortium (ExAC) 0.00200

Trans-Omics for Precision Medicine (TOPMed) 0.00204

Links

ClinGen: CA10184571 dbSNP: rs11557600 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.
TCN2		-	-	GRCh38 GRCh37	646	713

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	Benign (1)	criteria provided, single submitter	Aug 15, 2017	RCV000507154.9
not provided	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000585117.29
Transcobalamin II deficiency	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jan 30, 2024	RCV000624935.23
TCN2-related disorder	Benign (1)	no assertion criteria provided	Jul 1, 2019	RCV003925511.2

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.
Likely benign (Jun 02, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Transcobalamin II deficiency Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743135.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018
Likely benign (Jul 05, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Transcobalamin II deficiency Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744145.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018
Benign (Aug 15, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not Specified Affected status: unknown Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV000864382.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Comment: BS1, BS2, BP1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult … (more) BS1, BS2, BP1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is a missense alteration in a gene for which primarily truncating variants are known to cause disease, and is predicted to be tolerated by multiple functional prediction tools. (less)
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Transcobalamin II deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001309418.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 22188304‚ 12194912 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
Benign (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Transcobalamin II deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000756653.7 First in ClinVar: Apr 20, 2018 Last updated: Feb 20, 2024
Likely benign (Oct 03, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Transcobalamin II deficiency Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000605342.4 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005210298.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Dec 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000693081.30 First in ClinVar: Mar 03, 2018 Last updated: Oct 20, 2024	Comment: TCN2: BP4 Number of individuals with the variant: 2
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797707.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (Jul 01, 2019)	no assertion criteria provided Method: clinical testing	TCN2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004742018.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Comment:

BS1, BS2, BP1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is a missense alteration in a gene for which primarily truncating variants are known to cause disease, and is predicted to be tolerated by multiple functional prediction tools.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

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

Title	Author	Journal	Year	Link
Polymorphisms in transcobalamin II gene is associated with coronary artery disease in Indian population.	Garg G	Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals	2012	PMID: 22188304
Polymorphisms in the transcobalamin gene: association with plasma homocysteine in healthy individuals and vascular disease patients.	Lievers KJ	Clinical chemistry	2002	PMID: 12194912

Text-mined citations for rs11557600 ...

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_000355.4(TCN2):c.280G>A (p.Gly94Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs11557600 ...