VCV000180150.17 - ClinVar

NM_013251.4(TAC3):c.248A>G (p.His83Arg)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_013251.4(TAC3):c.248A>G (p.His83Arg)

Variation ID: 180150 Accession: VCV000180150.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.3 12: 57012866 (GRCh38) [ NCBI UCSC ] 12: 57406650 (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	Feb 2, 2015	Oct 20, 2024	Oct 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_013251.4:c.248A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_037383.1:p.His83Arg	missense
NM_001178054.2:c.239-414A>G		intron variant
NR_033654.2:n.396A>G		non-coding transcript variant
NR_135164.2:n.396A>G		non-coding transcript variant
NR_135165.2:n.396A>G		non-coding transcript variant
NC_000012.12:g.57012866T>C
NC_000012.11:g.57406650T>C
NG_021398.1:g.8695A>G

... more HGVS ... less HGVS

Protein change

H83R

Other names

Canonical SPDI

NC_000012.12:57012865:T:C

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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Exome Aggregation Consortium (ExAC) 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00019

The Genome Aggregation Database (gnomAD) 0.00010

Links

ClinGen: CA185877 dbSNP: rs143862988 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.
TAC3		-	-	GRCh38 GRCh37	26	34

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.
Delayed puberty	Likely pathogenic (1)	criteria provided, single submitter	Nov 1, 2014	RCV000156948.1
Infertility disorder	Pathogenic (1)	no assertion criteria provided	-	RCV001327940.1
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV001857549.15

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 pathogenic (Nov 01, 2014)	criteria provided, single submitter (Submitter's publication) Method: case-control	Delayed puberty Affected status: yes Allele origin: unknown	Chan Lab, Boston Children's Hospital Accession: SCV000206669.2 First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015	Number of individuals with the variant: 1
Uncertain significance (Oct 14, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002170237.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 25636053‚ 29419413 Comment: This sequence change replaces histidine with arginine at codon 83 of the TAC3 protein (p.His83Arg). The histidine residue is highly conserved and there is a … (more) This sequence change replaces histidine with arginine at codon 83 of the TAC3 protein (p.His83Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs143862988, ExAC 0.05%). This missense change has been observed in individual(s) with clinical features of TAC3-related conditions (PMID: 25636053, 29419413). ClinVar contains an entry for this variant (Variation ID: 180150). 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: "Benign"; Align-GVGD: "Class C25"). 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 (Oct 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: SCV004133497.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (-)	no assertion criteria provided Method: provider interpretation	Infertility disorder Affected status: yes Allele origin: germline	MAGI's Lab - Research, MAGI Group Accession: SCV001432718.1 First in ClinVar: Mar 18, 2021 Last updated: Mar 18, 2021

Comment:

This sequence change replaces histidine with arginine at codon 83 of the TAC3 protein (p.His83Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs143862988, ExAC 0.05%). This missense change has been observed in individual(s) with clinical features of TAC3-related conditions (PMID: 25636053, 29419413). ClinVar contains an entry for this variant (Variation ID: 180150). 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: "Benign"; Align-GVGD: "Class C25"). 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.

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
Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.	Cassatella D	European journal of endocrinology	2018	PMID: 29419413
A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism.	Zhu J	The Journal of clinical endocrinology and metabolism	2015	PMID: 25636053

Text-mined citations for rs143862988 ...

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_013251.4(TAC3):c.248A>G (p.His83Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs143862988 ...