VCV001695465.4 - ClinVar

NM_000516.7(GNAS):c.389A>G (p.Tyr130Cys)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000516.7(GNAS):c.389A>G (p.Tyr130Cys)

Variation ID: 1695465 Accession: VCV001695465.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.32 20: 58903748 (GRCh38) [ NCBI UCSC ] 20: 57478803 (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 18, 2022	Dec 17, 2023	Aug 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000516.7:c.389A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000507.1:p.Tyr130Cys	missense
NM_016592.5:c.*295A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_080425.4:c.2318A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_536350.2:p.Tyr773Cys	missense
NM_001077488.5:c.392A>G	NP_001070956.1:p.Tyr131Cys	missense
NM_001077489.4:c.344A>G	NP_001070957.1:p.Tyr115Cys	missense
NM_001077490.3:c.*250A>G		3 prime UTR
NM_001309840.2:c.212A>G	NP_001296769.1:p.Tyr71Cys	missense
NM_001309861.2:c.212A>G	NP_001296790.1:p.Tyr71Cys	missense
NM_080426.4:c.347A>G	NP_536351.1:p.Tyr116Cys	missense
NC_000020.11:g.58903748A>G
NC_000020.10:g.57478803A>G
NG_016194.2:g.69009A>G

... more HGVS ... less HGVS

Protein change

Y115C, Y116C, Y130C, Y131C, Y71C, Y773C

Other names

Canonical SPDI

NC_000020.11:58903747: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: rs2146184314 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.
GNAS		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	941	1097

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	Pathogenic (1)	criteria provided, single submitter	Aug 11, 2023	RCV002265100.4
Pseudohypoparathyroidism type I A	Uncertain significance (1)	criteria provided, single submitter	Feb 14, 2023	RCV003447623.2

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.
Pathogenic (Aug 11, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002546632.3 First in ClinVar: Jul 18, 2022 Last updated: Aug 18, 2023	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33730787) (less)
Uncertain significance (Feb 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pseudohypoparathyroidism type I A (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004175835.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: The missense c.389A>G(p.Tyr130Cys) variant in GNAS gene has been reported previously in heterozygous state in an individual (as a De-novo variant) affected with Pseudohypoparathyroidism type … (more) The missense c.389A>G(p.Tyr130Cys) variant in GNAS gene has been reported previously in heterozygous state in an individual (as a De-novo variant) affected with Pseudohypoparathyroidism type 1A (Kotanidou EP, et. al., 2021). The p.Tyr130Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Tyr130Cys in GNAS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Tyr at position 130 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies are required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). (less)

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33730787)

Comment:

The missense c.389A>G(p.Tyr130Cys) variant in GNAS gene has been reported previously in heterozygous state in an individual (as a De-novo variant) affected with Pseudohypoparathyroidism type 1A (Kotanidou EP, et. al., 2021). The p.Tyr130Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Tyr130Cys in GNAS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Tyr at position 130 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies are required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

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 rs2146184314 ...

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 Apr 06, 2024

ClinVar Genomic variation as it relates to human health

NM_000516.7(GNAS):c.389A>G (p.Tyr130Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2146184314 ...