VCV000207518.49 - ClinVar

NM_001199107.2(TBC1D24):c.179G>A (p.Arg60Gln)

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.

(8)

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(4); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001199107.2(TBC1D24):c.179G>A (p.Arg60Gln)

Variation ID: 207518 Accession: VCV000207518.49

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 2496327 (GRCh38) [ NCBI UCSC ] 16: 2546328 (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	Mar 8, 2017	Oct 20, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001199107.2:c.179G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001186036.1:p.Arg60Gln	missense
NM_020705.3:c.179G>A	NP_065756.1:p.Arg60Gln	missense
NC_000016.10:g.2496327G>A
NC_000016.9:g.2546328G>A
NG_028170.1:g.26182G>A

... more HGVS ... less HGVS

Protein change

R60Q

Other names

p.R60Q:CGG>CAG

Canonical SPDI

NC_000016.10:2496326: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00026

The Genome Aggregation Database (gnomAD) 0.00031

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00039

Links

ClinGen: CA319074 dbSNP: rs200226466 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.
TBC1D24		-	-	GRCh38 GRCh37	933	991

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	Likely benign (1)	criteria provided, single submitter	Sep 17, 2015	RCV000189705.9
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Oct 1, 2023	RCV000431937.30
Familial infantile myoclonic epilepsy	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001120140.5
Autosomal dominant nonsyndromic hearing loss 65 Caused by mutation in the TBC1 domain family, member 24 Developmental and epileptic encephalopathy, 1	Likely benign (1)	criteria provided, single submitter	Jan 8, 2024	RCV000651565.12
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Apr 3, 2018	RCV002408852.3
TBC1D24-related disorder	Uncertain significance (1)	no assertion criteria provided	Jan 4, 2024	RCV004553042.2

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 (Jun 27, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511000.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Converted during submission to Uncertain significance.
Likely benign (Sep 17, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000270887.3 First in ClinVar: May 29, 2016 Last updated: Apr 09, 2018	Comment: p.Arg60Gln in exon 2 of TBC1D24: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including … (more) p.Arg60Gln in exon 2 of TBC1D24: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, bushbaby and shrew have a glutamine (Gln) at this position despite high ne arby amino acid conservation. In addition, computational prediction tools sugges t that the p.Arg60Gln variant may not impact the protein and the variant also be en identified in 0.03% (22/65926) of European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200226466). (less) Number of individuals with the variant: 2
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial infantile myoclonic epilepsy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001278605.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Jan 04, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000243352.9 First in ClinVar: Aug 07, 2015 Last updated: Apr 09, 2018	Comment: This variant is associated with the following publications: (PMID: 27281533)
Likely benign (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Caused by mutation in the TBC1 domain family, member 24 Developmental and epileptic encephalopathy, 1 Autosomal dominant nonsyndromic hearing loss 65 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000773419.8 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
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: SCV000892446.28 First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024	Comment: TBC1D24: PM2:Supporting, BP4 Number of individuals with the variant: 8
Uncertain significance (Apr 03, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002717284.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.R60Q variant (also known as c.179G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide … (more) The p.R60Q variant (also known as c.179G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 179. The arginine at codon 60 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jan 04, 2024)	no assertion criteria provided Method: clinical testing	TBC1D24-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119831.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The TBC1D24 c.179G>A variant is predicted to result in the amino acid substitution p.Arg60Gln. To our knowledge, this variant has not been reported in the … (more) The TBC1D24 c.179G>A variant is predicted to result in the amino acid substitution p.Arg60Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

p.Arg60Gln in exon 2 of TBC1D24: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, bushbaby and shrew have a glutamine (Gln) at this position despite high ne arby amino acid conservation. In addition, computational prediction tools sugges t that the p.Arg60Gln variant may not impact the protein and the variant also be en identified in 0.03% (22/65926) of European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200226466).

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The p.R60Q variant (also known as c.179G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 179. The arginine at codon 60 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

The TBC1D24 c.179G>A variant is predicted to result in the amino acid substitution p.Arg60Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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 rs200226466 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001199107.2(TBC1D24):c.179G>A (p.Arg60Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200226466 ...