VCV001400280.7 - ClinVar

NM_198252.3(GSN):c.62G>A (p.Arg21His)

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_198252.3(GSN):c.62G>A (p.Arg21His)

Variation ID: 1400280 Accession: VCV001400280.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q33.2 9: 121302033 (GRCh38) [ NCBI UCSC ] 9: 124064311 (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 28, 2022	May 1, 2024	Mar 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_198252.3:c.62G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_937895.1:p.Arg21His	missense
NM_000177.5:c.215G>A	NP_000168.1:p.Arg72His	missense
NM_001127662.2:c.62G>A	NP_001121134.1:p.Arg21His	missense
NM_001127663.2:c.170G>A	NP_001121135.2:p.Arg57His	missense
NM_001127664.2:c.62G>A	NP_001121136.1:p.Arg21His	missense
NM_001127665.2:c.62G>A	NP_001121137.1:p.Arg21His	missense
NM_001127666.2:c.95G>A	NP_001121138.1:p.Arg32His	missense
NM_001127667.2:c.95G>A	NP_001121139.1:p.Arg32His	missense
NM_001258029.2:c.113G>A	NP_001244958.1:p.Arg38His	missense
NM_001258030.2:c.86G>A	NP_001244959.1:p.Arg29His	missense
NM_001353053.1:c.62G>A	NP_001339982.1:p.Arg21His	missense
NM_001353054.1:c.62G>A	NP_001339983.1:p.Arg21His	missense
NM_001353055.2:c.62G>A	NP_001339984.1:p.Arg21His	missense
NM_001353056.2:c.62G>A	NP_001339985.1:p.Arg21His	missense
NM_001353057.2:c.62G>A	NP_001339986.1:p.Arg21His	missense
NM_001353058.2:c.62G>A	NP_001339987.1:p.Arg21His	missense
NM_001353059.2:c.62G>A	NP_001339988.1:p.Arg21His	missense
NM_001353060.2:c.62G>A	NP_001339989.1:p.Arg21His	missense
NM_001353061.2:c.62G>A	NP_001339990.1:p.Arg21His	missense
NM_001353062.1:c.62G>A	NP_001339991.1:p.Arg21His	missense
NM_001353063.2:c.95G>A	NP_001339992.1:p.Arg32His	missense
NM_001353064.2:c.95G>A	NP_001339993.1:p.Arg32His	missense
NM_001353065.2:c.95G>A	NP_001339994.1:p.Arg32His	missense
NM_001353066.2:c.95G>A	NP_001339995.1:p.Arg32His	missense
NM_001353067.2:c.95G>A	NP_001339996.1:p.Arg32His	missense
NM_001353068.2:c.95G>A	NP_001339997.1:p.Arg32His	missense
NM_001353069.2:c.95G>A	NP_001339998.1:p.Arg32His	missense
NM_001353070.2:c.95G>A	NP_001339999.1:p.Arg32His	missense
NM_001353071.2:c.95G>A	NP_001340000.1:p.Arg32His	missense
NM_001353072.2:c.95G>A	NP_001340001.1:p.Arg32His	missense
NM_001353073.2:c.95G>A	NP_001340002.1:p.Arg32His	missense
NM_001353074.2:c.95G>A	NP_001340003.1:p.Arg32His	missense
NM_001353075.1:c.95G>A	NP_001340004.1:p.Arg32His	missense
NM_001353076.2:c.134G>A	NP_001340005.1:p.Arg45His	missense
NM_001353077.1:c.95G>A	NP_001340006.1:p.Arg32His	missense
NM_001353078.2:c.-458-878G>A		intron variant
NC_000009.12:g.121302033G>A
NC_000009.11:g.124064311G>A
NG_012872.2:g.105952G>A

... more HGVS ... less HGVS

Protein change

R21H, R32H, R57H, R29H, R38H, R45H, R72H

Other names

Canonical SPDI

NC_000009.12:121302032: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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs766916675 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.
GSN		-	-	GRCh38 GRCh37	723	759

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 provided	Uncertain significance (1)	criteria provided, single submitter	Mar 23, 2023	RCV001918113.6
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Dec 10, 2019	RCV002425206.2

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 (Mar 23, 2023)	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: SCV002174370.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Comment: 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 … (more) 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1400280). This variant has not been reported in the literature in individuals affected with GSN-related conditions. This variant is present in population databases (rs766916675, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 72 of the GSN protein (p.Arg72His). (less)
Uncertain significance (Dec 10, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002728466.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.R72H variant (also known as c.215G>A), located in coding exon 2 of the GSN gene, results from a G to A substitution at nucleotide … (more) The p.R72H variant (also known as c.215G>A), located in coding exon 2 of the GSN gene, results from a G to A substitution at nucleotide position 215. The arginine at codon 72 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1400280). This variant has not been reported in the literature in individuals affected with GSN-related conditions. This variant is present in population databases (rs766916675, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 72 of the GSN protein (p.Arg72His).

Comment:

The p.R72H variant (also known as c.215G>A), located in coding exon 2 of the GSN gene, results from a G to A substitution at nucleotide position 215. The arginine at codon 72 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 rs766916675 ...

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_198252.3(GSN):c.62G>A (p.Arg21His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs766916675 ...