VCV000947691.10 - ClinVar

NM_000548.5(TSC2):c.5171A>G (p.Gln1724Arg)

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.

(2)

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_000548.5(TSC2):c.5171A>G (p.Gln1724Arg)

Variation ID: 947691 Accession: VCV000947691.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 2088237 (GRCh38) [ NCBI UCSC ] 16: 2138238 (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	Jul 16, 2020	May 1, 2024	Apr 13, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000548.5:c.5171A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000539.2:p.Gln1724Arg	missense
NM_001077183.3:c.4970A>G	NP_001070651.1:p.Gln1657Arg	missense
NM_001114382.3:c.5102A>G	NP_001107854.1:p.Gln1701Arg	missense
NM_001318827.2:c.4862A>G	NP_001305756.1:p.Gln1621Arg	missense
NM_001318829.2:c.4826A>G	NP_001305758.1:p.Gln1609Arg	missense
NM_001318831.2:c.4439A>G	NP_001305760.1:p.Gln1480Arg	missense
NM_001318832.2:c.5003A>G	NP_001305761.1:p.Gln1668Arg	missense
NM_001363528.2:c.4973A>G	NP_001350457.1:p.Gln1658Arg	missense
NM_001370404.1:c.5039A>G	NP_001357333.1:p.Gln1680Arg	missense
NM_001370405.1:c.5032-2A>G		splice acceptor
NM_001406663.1:c.5168A>G	NP_001393592.1:p.Gln1723Arg	missense
NM_001406664.1:c.5099A>G	NP_001393593.1:p.Gln1700Arg	missense
NM_001406665.1:c.5093A>G	NP_001393594.1:p.Gln1698Arg	missense
NM_001406667.1:c.5063A>G	NP_001393596.1:p.Gln1688Arg	missense
NM_001406668.1:c.5060A>G	NP_001393597.1:p.Gln1687Arg	missense
NM_001406670.1:c.4991A>G	NP_001393599.1:p.Gln1664Arg	missense
NM_001406671.1:c.4961A>G	NP_001393600.1:p.Gln1654Arg	missense
NM_001406673.1:c.4958A>G	NP_001393602.1:p.Gln1653Arg	missense
NM_001406675.1:c.4955A>G	NP_001393604.1:p.Gln1652Arg	missense
NM_001406676.1:c.4952A>G	NP_001393605.1:p.Gln1651Arg	missense
NM_001406677.1:c.4913A>G	NP_001393606.1:p.Gln1638Arg	missense
NM_001406678.1:c.4859A>G	NP_001393607.1:p.Gln1620Arg	missense
NM_001406679.1:c.4823A>G	NP_001393608.1:p.Gln1608Arg	missense
NM_001406680.1:c.4571A>G	NP_001393609.1:p.Gln1524Arg	missense
NM_001406681.1:c.4511A>G	NP_001393610.1:p.Gln1504Arg	missense
NM_001406682.1:c.4502A>G	NP_001393611.1:p.Gln1501Arg	missense
NM_001406683.1:c.4502A>G	NP_001393612.1:p.Gln1501Arg	missense
NM_001406684.1:c.4499A>G	NP_001393613.1:p.Gln1500Arg	missense
NM_001406685.1:c.4373A>G	NP_001393614.1:p.Gln1458Arg	missense
NM_001406686.1:c.4373A>G	NP_001393615.1:p.Gln1458Arg	missense
NM_001406687.1:c.4370A>G	NP_001393616.1:p.Gln1457Arg	missense
NM_001406688.1:c.4370A>G	NP_001393617.1:p.Gln1457Arg	missense
NM_001406689.1:c.3758A>G	NP_001393618.1:p.Gln1253Arg	missense
NM_001406690.1:c.3698A>G	NP_001393619.1:p.Gln1233Arg	missense
NM_001406691.1:c.3695A>G	NP_001393620.1:p.Gln1232Arg	missense
NM_001406692.1:c.3629A>G	NP_001393621.1:p.Gln1210Arg	missense
NM_001406693.1:c.3629A>G	NP_001393622.1:p.Gln1210Arg	missense
NM_001406694.1:c.3629A>G	NP_001393623.1:p.Gln1210Arg	missense
NM_001406695.1:c.3626A>G	NP_001393624.1:p.Gln1209Arg	missense
NM_001406696.1:c.3626A>G	NP_001393625.1:p.Gln1209Arg	missense
NM_001406697.1:c.3626A>G	NP_001393626.1:p.Gln1209Arg	missense
NM_001406698.1:c.3368A>G	NP_001393627.1:p.Gln1123Arg	missense
NM_021055.3:c.5042A>G	NP_066399.2:p.Gln1681Arg	missense
NR_176225.1:n.5123A>G		non-coding transcript variant
NR_176226.1:n.5371A>G		non-coding transcript variant
NR_176227.1:n.5299A>G		non-coding transcript variant
NR_176228.1:n.5120A>G		non-coding transcript variant
NR_176229.1:n.5045A>G		non-coding transcript variant
NC_000016.10:g.2088237A>G
NC_000016.9:g.2138238A>G
NG_005895.1:g.43932A>G
NG_008617.1:g.54984T>C
LRG_487:g.43932A>G
LRG_487t1:c.5171A>G	LRG_487p1:p.Gln1724Arg

... more HGVS ... less HGVS

Protein change

Q1609R, Q1621R, Q1680R, Q1668R, Q1681R, Q1657R, Q1701R, Q1724R, Q1480R, Q1658R, Q1123R, Q1209R, Q1210R, Q1232R, Q1233R, Q1253R, Q1457R, Q1458R, Q1500R, Q1501R, Q1504R, Q1524R, Q1608R, Q1620R, Q1638R, Q1651R, Q1652R, Q1653R, Q1654R, Q1664R, Q1687R, Q1688R, Q1698R, Q1700R, Q1723R

Other names

Canonical SPDI

NC_000016.10:2088236:A:G

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

dbSNP: rs923367492 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.
TSC2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	10752	10951

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.
Tuberous sclerosis 2	Uncertain significance (1)	criteria provided, single submitter	Apr 13, 2022	RCV001218813.8
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Nov 18, 2020	RCV002339576.2

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 (Apr 13, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tuberous sclerosis 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001390717.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Comment: This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1724 of the TSC2 protein (p.Gln1724Arg). … (more) This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1724 of the TSC2 protein (p.Gln1724Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 947691). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 (Nov 18, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002644983.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.Q1724R variant (also known as c.5171A>G), located in coding exon 40 of the TSC2 gene, results from an A to G substitution at nucleotide … (more) The p.Q1724R variant (also known as c.5171A>G), located in coding exon 40 of the TSC2 gene, results from an A to G substitution at nucleotide position 5171. The glutamine at codon 1724 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1724 of the TSC2 protein (p.Gln1724Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 947691). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 p.Q1724R variant (also known as c.5171A>G), located in coding exon 40 of the TSC2 gene, results from an A to G substitution at nucleotide position 5171. The glutamine at codon 1724 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, 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 rs923367492 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000548.5(TSC2):c.5171A>G (p.Gln1724Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs923367492 ...