The GNAS c.601C>T (p.Arg201Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in numerous patients with McCune Albright Syndrome, with/without polyostotic fibrous dysplasia (Sargin H et al., PMID: 16543670; Lumborso S et al., PMID: 15126527, Caspari L et al., PMID: 22692721; Narumi S et al., PMID: 23536913). This variant is only observed on 2/152140 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GNAS function. This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters (ClinVar Variation ID: 15933). Functional studies show that the GNAS c.601C>T (p.Arg201Cys) variant leads to elevated expression of Wnt and increases the phosphorylation of ERK1/2 MAPK, cell proliferation, and tumor growth in animal models, indicating that this variant impacts protein function (Wilson CH et al., PMID: 20531296; More A et al., PMID: 35879396). Other variants in the same codon, including p.Arg201His, have been reported in affected individuals and are considered pathogenic/likely pathogenic (Riminucci M et al., PMID: 10571700, Fragoso MCBV et al., PMID: 12727968, ClinVar ID's: 15945, 210045, 15937, 15934). GNAS c.601C>T (p.Arg201Cys) is one of the most frequently occurring variants in McCune Albright Syndrome (Lumborso S et al., PMID: 15126527; Narumi S et al., PMID: 23536913; Shi RR et al., PMID: 23503642). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the GNAS c.601C>T (p.Arg201Cys) variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000516.7(GNAS):c.601C>T (p.Arg201Cys)
Germline
Classification
Help
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.
(21)
Help
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.
Pathogenic/Likely pathogenic
21
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.
Oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_000516.7(GNAS):c.601C>T (p.Arg201Cys)
Variation ID: 15933 Accession: VCV000015933.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 20q13.32 20: 58909365 (GRCh38) [ NCBI UCSC ] 20: 57484420 (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 Oct 1, 2015 Oct 13, 2024 Sep 22, 2024 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000516.7:c.601C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000507.1:p.Arg201Cys missense NM_016592.5:c.*507C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_080425.4:c.2530C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_536350.2:p.Arg844Cys missense NM_001077488.5:c.604C>T NP_001070956.1:p.Arg202Cys missense NM_001077489.4:c.556C>T NP_001070957.1:p.Arg186Cys missense NM_001077490.3:c.*462C>T 3 prime UTR NM_001309840.2:c.424C>T NP_001296769.1:p.Arg142Cys missense NM_001309861.2:c.424C>T NP_001296790.1:p.Arg142Cys missense NM_080425.3:c.2530C>T NM_080426.4:c.559C>T NP_536351.1:p.Arg187Cys missense NC_000020.11:g.58909365C>T NC_000020.10:g.57484420C>T NG_016194.2:g.74626C>T P63092:p.Arg201Cys - Protein change
- R201C, R202C, R844C, R186C, R142C, R187C
- Other names
- -
- Canonical SPDI
- NC_000020.11:58909364:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
936 | 1092 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, single submitter
|
Sep 8, 2023 | RCV000017287.15 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 23, 2014 | RCV000017289.13 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000421422.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000427542.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000422043.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000431495.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000432295.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000429524.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000437784.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000444862.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000420084.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000443647.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000439728.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 23, 2014 | RCV000508635.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 17, 2023 | RCV002513071.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 23, 2014 | RCV004558264.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 22, 2024 | RCV004760335.1 | |
| click to load more click to collapse | ||||
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
(Sep 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
McCune-Albright syndrome
Affected status: yes
Allele origin:
somatic
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV004176911.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
The GNAS c.601C>T (p.Arg201Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in numerous patients with McCune … (more)
The GNAS c.601C>T (p.Arg201Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in numerous patients with McCune Albright Syndrome, with/without polyostotic fibrous dysplasia (Sargin H et al., PMID: 16543670; Lumborso S et al., PMID: 15126527, Caspari L et al., PMID: 22692721; Narumi S et al., PMID: 23536913). This variant is only observed on 2/152140 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GNAS function. This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters (ClinVar Variation ID: 15933). Functional studies show that the GNAS c.601C>T (p.Arg201Cys) variant leads to elevated expression of Wnt and increases the phosphorylation of ERK1/2 MAPK, cell proliferation, and tumor growth in animal models, indicating that this variant impacts protein function (Wilson CH et al., PMID: 20531296; More A et al., PMID: 35879396). Other variants in the same codon, including p.Arg201His, have been reported in affected individuals and are considered pathogenic/likely pathogenic (Riminucci M et al., PMID: 10571700, Fragoso MCBV et al., PMID: 12727968, ClinVar ID's: 15945, 210045, 15937, 15934). GNAS c.601C>T (p.Arg201Cys) is one of the most frequently occurring variants in McCune Albright Syndrome (Lumborso S et al., PMID: 15126527; Narumi S et al., PMID: 23536913; Shi RR et al., PMID: 23503642). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the GNAS c.601C>T (p.Arg201Cys) variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003272248.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg201 amino acid residue in GNAS. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg201 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15126527, 27506760). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GNAS function (PMID: 2549426). 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 expected to disrupt GNAS protein function. ClinVar contains an entry for this variant (Variation ID: 15933). This missense change has been observed in individual(s) with McCune-Albright syndrome, as a somatic mosaic variant (PMID: 16543670, 17873334, 20197676, 27506760). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the GNAS protein (p.Arg201Cys). (less)
|
|
|
Pathogenic
(Mar 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198404.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Likely pathogenic
(Sep 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudohypoparathyroidism type 1B
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005374279.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505260.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Adrenal cortex carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506433.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Pancreatic adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506432.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Hepatocellular carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506434.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of uterine cervix
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506435.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant melanoma of skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506436.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506437.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Gastric adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506439.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506438.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506440.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Breast neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506441.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(May 23, 2014)
|
no assertion criteria provided
Method: literature only
|
ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000188577.2
First in ClinVar: Aug 25, 2014 Last updated: Sep 30, 2017 |
Comment on evidence:
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon … (more)
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon 8 of the GNAS gene. Two patients carried an arg201-to-cys substitution (R201C); the other 2 carried an R201H substitution (139320.0009). Tissues analyzed included affected endocrine organs, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved in the McCune-Albright syndrome. In each patient the proportion of cells affected varied from tissue to tissue. In 2 endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. Candeliere et al. (1995) found the R201C mutation in a 14-year-old boy who had previously been reported as a case of panostotic fibrous dysplasia (see 174800). Landis et al. (1989) identified somatic gain-of-function mutations in the GNAS1 gene in 4 of 8 growth hormone-secreting pituitary tumors (PITA3; 617686) surgically removed from patients with acromegaly. Two tumors contained a C-to-T transition resulting in an R201C substitution. The other 2 tumors had an R201H substitution (139320.0009) and a Q227R substitution (139320.0010), respectively. All the mutations resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like dominantly acting oncogenes. Yang et al. (1996) identified somatic mutations at GNAS codon 201 in 9 of 21 pituitary adenomas derived from Korean patients with acromegaly. Eight tumors had the R201C mutation and 1 had an R201S substitution (139320.0013). Clinically, patients with the GNAS mutations were older and responded better to octreotide-induced growth hormone suppression than those without mutations. Collins et al. (2003) identified an R201C mutation in thyroid carcinoma derived from a patient with McCune-Albright syndrome. Fragoso et al. (1998) identified a somatic R201C mutation in 4 (66.6%) of 14 human sex cord stromal tumors, including ovarian and testicular Leydig cell tumors. In contrast, no GIP2 (139360) mutations were found in any of the sex cord stromal tumors studied. Kalfa et al. (2006) detected the R201C mutation in 8 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. Patients with a hyperactivated G-alpha-s exhibited a significantly more advanced tumor (p less than 0.05) because 7 of them (77.7%) were staged as Ic or had had a recurrence. In tumor tissue derived from 6 unrelated patients with ACTH-independent adrenocortical hyperplasia (AIMAH; 219080) Sato et al. (2014) identified a somatic heterozygous c.556C-T transition in the GNAS gene, resulting in an R201C substitution in the switch I domain. Tumor tissue from 4 additional patients carried a somatic GNAS mutation affecting the same codon (R201H; 139320.0009). GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. (less)
|
|
|
Pathogenic
(May 23, 2014)
|
no assertion criteria provided
Method: literature only
|
PITUITARY ADENOMA 3, GROWTH HORMONE-SECRETING, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000605824.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Comment on evidence:
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon … (more)
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon 8 of the GNAS gene. Two patients carried an arg201-to-cys substitution (R201C); the other 2 carried an R201H substitution (139320.0009). Tissues analyzed included affected endocrine organs, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved in the McCune-Albright syndrome. In each patient the proportion of cells affected varied from tissue to tissue. In 2 endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. Candeliere et al. (1995) found the R201C mutation in a 14-year-old boy who had previously been reported as a case of panostotic fibrous dysplasia (see 174800). Landis et al. (1989) identified somatic gain-of-function mutations in the GNAS1 gene in 4 of 8 growth hormone-secreting pituitary tumors (PITA3; 617686) surgically removed from patients with acromegaly. Two tumors contained a C-to-T transition resulting in an R201C substitution. The other 2 tumors had an R201H substitution (139320.0009) and a Q227R substitution (139320.0010), respectively. All the mutations resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like dominantly acting oncogenes. Yang et al. (1996) identified somatic mutations at GNAS codon 201 in 9 of 21 pituitary adenomas derived from Korean patients with acromegaly. Eight tumors had the R201C mutation and 1 had an R201S substitution (139320.0013). Clinically, patients with the GNAS mutations were older and responded better to octreotide-induced growth hormone suppression than those without mutations. Collins et al. (2003) identified an R201C mutation in thyroid carcinoma derived from a patient with McCune-Albright syndrome. Fragoso et al. (1998) identified a somatic R201C mutation in 4 (66.6%) of 14 human sex cord stromal tumors, including ovarian and testicular Leydig cell tumors. In contrast, no GIP2 (139360) mutations were found in any of the sex cord stromal tumors studied. Kalfa et al. (2006) detected the R201C mutation in 8 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. Patients with a hyperactivated G-alpha-s exhibited a significantly more advanced tumor (p less than 0.05) because 7 of them (77.7%) were staged as Ic or had had a recurrence. In tumor tissue derived from 6 unrelated patients with ACTH-independent adrenocortical hyperplasia (AIMAH; 219080) Sato et al. (2014) identified a somatic heterozygous c.556C-T transition in the GNAS gene, resulting in an R201C substitution in the switch I domain. Tumor tissue from 4 additional patients carried a somatic GNAS mutation affecting the same codon (R201H; 139320.0009). GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. (less)
|
|
|
Pathogenic
(May 23, 2014)
|
no assertion criteria provided
Method: literature only
|
SEX CORD STROMAL TUMOR, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000037561.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 30, 2017 |
Comment on evidence:
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon … (more)
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon 8 of the GNAS gene. Two patients carried an arg201-to-cys substitution (R201C); the other 2 carried an R201H substitution (139320.0009). Tissues analyzed included affected endocrine organs, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved in the McCune-Albright syndrome. In each patient the proportion of cells affected varied from tissue to tissue. In 2 endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. Candeliere et al. (1995) found the R201C mutation in a 14-year-old boy who had previously been reported as a case of panostotic fibrous dysplasia (see 174800). Landis et al. (1989) identified somatic gain-of-function mutations in the GNAS1 gene in 4 of 8 growth hormone-secreting pituitary tumors (PITA3; 617686) surgically removed from patients with acromegaly. Two tumors contained a C-to-T transition resulting in an R201C substitution. The other 2 tumors had an R201H substitution (139320.0009) and a Q227R substitution (139320.0010), respectively. All the mutations resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like dominantly acting oncogenes. Yang et al. (1996) identified somatic mutations at GNAS codon 201 in 9 of 21 pituitary adenomas derived from Korean patients with acromegaly. Eight tumors had the R201C mutation and 1 had an R201S substitution (139320.0013). Clinically, patients with the GNAS mutations were older and responded better to octreotide-induced growth hormone suppression than those without mutations. Collins et al. (2003) identified an R201C mutation in thyroid carcinoma derived from a patient with McCune-Albright syndrome. Fragoso et al. (1998) identified a somatic R201C mutation in 4 (66.6%) of 14 human sex cord stromal tumors, including ovarian and testicular Leydig cell tumors. In contrast, no GIP2 (139360) mutations were found in any of the sex cord stromal tumors studied. Kalfa et al. (2006) detected the R201C mutation in 8 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. Patients with a hyperactivated G-alpha-s exhibited a significantly more advanced tumor (p less than 0.05) because 7 of them (77.7%) were staged as Ic or had had a recurrence. In tumor tissue derived from 6 unrelated patients with ACTH-independent adrenocortical hyperplasia (AIMAH; 219080) Sato et al. (2014) identified a somatic heterozygous c.556C-T transition in the GNAS gene, resulting in an R201C substitution in the switch I domain. Tumor tissue from 4 additional patients carried a somatic GNAS mutation affecting the same codon (R201H; 139320.0009). GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. (less)
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Pathogenic
(May 23, 2014)
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no assertion criteria provided
Method: literature only
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MCCUNE-ALBRIGHT SYNDROME, SOMATIC, MOSAIC
Affected status: not provided
Allele origin:
somatic
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OMIM
Accession: SCV000037559.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 30, 2017 |
Comment on evidence:
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon … (more)
In various tissues from 4 patients with McCune-Albright syndrome (174800), Weinstein et al. (1991) found 1 of 2 activating mutations within codon 201 in exon 8 of the GNAS gene. Two patients carried an arg201-to-cys substitution (R201C); the other 2 carried an R201H substitution (139320.0009). Tissues analyzed included affected endocrine organs, such as gonads, adrenal glands, thyroid, and pituitary, as well as tissues not classically involved in the McCune-Albright syndrome. In each patient the proportion of cells affected varied from tissue to tissue. In 2 endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Weinstein et al. (1991) concluded that somatic mutation of the GNAS gene early in embryogenesis resulted in the mosaic population of normal and mutant-bearing tissues that underlie the clinical manifestations of McCune-Albright syndrome. Candeliere et al. (1995) found the R201C mutation in a 14-year-old boy who had previously been reported as a case of panostotic fibrous dysplasia (see 174800). Landis et al. (1989) identified somatic gain-of-function mutations in the GNAS1 gene in 4 of 8 growth hormone-secreting pituitary tumors (PITA3; 617686) surgically removed from patients with acromegaly. Two tumors contained a C-to-T transition resulting in an R201C substitution. The other 2 tumors had an R201H substitution (139320.0009) and a Q227R substitution (139320.0010), respectively. All the mutations resulted in constitutive activation of Gs by inhibiting its GTPase activity and behaved like dominantly acting oncogenes. Yang et al. (1996) identified somatic mutations at GNAS codon 201 in 9 of 21 pituitary adenomas derived from Korean patients with acromegaly. Eight tumors had the R201C mutation and 1 had an R201S substitution (139320.0013). Clinically, patients with the GNAS mutations were older and responded better to octreotide-induced growth hormone suppression than those without mutations. Collins et al. (2003) identified an R201C mutation in thyroid carcinoma derived from a patient with McCune-Albright syndrome. Fragoso et al. (1998) identified a somatic R201C mutation in 4 (66.6%) of 14 human sex cord stromal tumors, including ovarian and testicular Leydig cell tumors. In contrast, no GIP2 (139360) mutations were found in any of the sex cord stromal tumors studied. Kalfa et al. (2006) detected the R201C mutation in 8 of 30 cases of juvenile ovarian granulosa cell tumor, the most common sex cord stromal tumor. Laser microdissection confirmed that the mutation was exclusively localized in the tumoral granulosa cells and was absent in the ovarian stroma. Patients with a hyperactivated G-alpha-s exhibited a significantly more advanced tumor (p less than 0.05) because 7 of them (77.7%) were staged as Ic or had had a recurrence. In tumor tissue derived from 6 unrelated patients with ACTH-independent adrenocortical hyperplasia (AIMAH; 219080) Sato et al. (2014) identified a somatic heterozygous c.556C-T transition in the GNAS gene, resulting in an R201C substitution in the switch I domain. Tumor tissue from 4 additional patients carried a somatic GNAS mutation affecting the same codon (R201H; 139320.0009). GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. (less)
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Pathogenic
(Feb 14, 2014)
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no assertion criteria provided
Method: clinical testing
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McCune-Albright syndrome
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804872.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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not provided
(-)
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no classification provided
Method: literature only
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McCune-Albright syndrome
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000246254.2
First in ClinVar: Oct 01, 2015 Last updated: Oct 01, 2022 |
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Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg201 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15126527, 27506760). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GNAS function (PMID: 2549426). 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 expected to disrupt GNAS protein function. ClinVar contains an entry for this variant (Variation ID: 15933). This missense change has been observed in individual(s) with McCune-Albright syndrome, as a somatic mosaic variant (PMID: 16543670, 17873334, 20197676, 27506760). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the GNAS protein (p.Arg201Cys).
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:
The GNAS c.601C>T (p.Arg201Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in numerous patients with McCune Albright Syndrome, with/without polyostotic fibrous dysplasia (Sargin H et al., PMID: 16543670; Lumborso S et al., PMID: 15126527, Caspari L et al., PMID: 22692721; Narumi S et al., PMID: 23536913). This variant is only observed on 2/152140 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GNAS function. This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters (ClinVar Variation ID: 15933). Functional studies show that the GNAS c.601C>T (p.Arg201Cys) variant leads to elevated expression of Wnt and increases the phosphorylation of ERK1/2 MAPK, cell proliferation, and tumor growth in animal models, indicating that this variant impacts protein function (Wilson CH et al., PMID: 20531296; More A et al., PMID: 35879396). Other variants in the same codon, including p.Arg201His, have been reported in affected individuals and are considered pathogenic/likely pathogenic (Riminucci M et al., PMID: 10571700, Fragoso MCBV et al., PMID: 12727968, ClinVar ID's: 15945, 210045, 15937, 15934). GNAS c.601C>T (p.Arg201Cys) is one of the most frequently occurring variants in McCune Albright Syndrome (Lumborso S et al., PMID: 15126527; Narumi S et al., PMID: 23536913; Shi RR et al., PMID: 23503642). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the GNAS c.601C>T (p.Arg201Cys) variant is classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg201 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15126527, 27506760). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GNAS function (PMID: 2549426). 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 expected to disrupt GNAS protein function. ClinVar contains an entry for this variant (Variation ID: 15933). This missense change has been observed in individual(s) with McCune-Albright syndrome, as a somatic mosaic variant (PMID: 16543670, 17873334, 20197676, 27506760). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the GNAS protein (p.Arg201Cys).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Fibrous Dysplasia / McCune-Albright Syndrome. | Adam MP | - | 2024 | PMID: 25719192 |
| Clinical and endocrine characteristics and genetic analysis of Korean children with McCune-Albright syndrome: a retrospective cohort study. | Cho EK | Orphanet journal of rare diseases | 2016 | PMID: 27506760 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. | Sato Y | Science (New York, N.Y.) | 2014 | PMID: 24855271 |
| Quantitative and sensitive detection of GNAS mutations causing mccune-albright syndrome with next generation sequencing. | Narumi S | PloS one | 2013 | PMID: 23536913 |
| GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. | Nault JC | Journal of hepatology | 2012 | PMID: 21835143 |
| Unusual phenotypical variations in a boy with McCune-Albright syndrome. | Mamkin I | Hormone research in paediatrics | 2010 | PMID: 20197676 |
| Genetic diagnosis of multiple affected tissues in a patient with McCune-Albright syndrome. | Zhou J | Endocrine | 2007 | PMID: 17873334 |
| A case of McCune-Albright syndrome associated with Gs alpha mutation in the bone tissue. | Sargin H | Endocrine journal | 2006 | PMID: 16543670 |
| Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? | Kalfa N | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16507630 |
| Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome--a European Collaborative Study. | Lumbroso S | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15126527 |
| Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gs alpha mutations. | Collins MT | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12970318 |
| Activating mutation of the stimulatory G protein (gsp) as a putative cause of ovarian and testicular human stromal Leydig cell tumors. | Fragoso MC | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9626141 |
| Characteristics of gsp-positive growth hormone-secreting pituitary tumors in Korean acromegalic patients. | Yang I | European journal of endocrinology | 1996 | PMID: 8766942 |
| Increased expression of the c-fos proto-oncogene in bone from patients with fibrous dysplasia. | Candeliere GA | The New England journal of medicine | 1995 | PMID: 7739708 |
| Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. | Weinstein LS | The New England journal of medicine | 1991 | PMID: 1944469 |
| GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. | Landis CA | Nature | 1989 | PMID: 2549426 |
| http://docm.genome.wustl.edu/variants/ENST00000354359:c.604C>T | - | - | - | - |
| http://docm.genome.wustl.edu/variants/ENST00000371100:c.2530C>T | - | - | - | - |
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Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
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Oncogenic
criteria provided, single submitter
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Jul 31, 2024 | RCV000420084.10 |
Submissions - Somatic
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Oncogenicity
Help
The submitted oncogenicity 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Oncogenic
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm
Affected status: unknown
Allele origin:
somatic
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094025.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
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Comment:
The GNAS c.601C>T (p.Arg201Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in numerous patients with McCune Albright Syndrome, with/without polyostotic fibrous dysplasia (Sargin H et al., PMID: 16543670; Lumborso S et al., PMID: 15126527, Caspari L et al., PMID: 22692721; Narumi S et al., PMID: 23536913). This variant is only observed on 2/152140 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GNAS function. This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters (ClinVar Variation ID: 15933). Functional studies show that the GNAS c.601C>T (p.Arg201Cys) variant leads to elevated expression of Wnt and increases the phosphorylation of ERK1/2 MAPK, cell proliferation, and tumor growth in animal models, indicating that this variant impacts protein function (Wilson CH et al., PMID: 20531296; More A et al., PMID: 35879396). Other variants in the same codon, including p.Arg201His, have been reported in affected individuals and are considered pathogenic/likely pathogenic (Riminucci M et al., PMID: 10571700, Fragoso MCBV et al., PMID: 12727968, ClinVar ID's: 15945, 210045, 15937, 15934). GNAS c.601C>T (p.Arg201Cys) is one of the most frequently occurring variants in McCune Albright Syndrome (Lumborso S et al., PMID: 15126527; Narumi S et al., PMID: 23536913; Shi RR et al., PMID: 23503642). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the GNAS c.601C>T (p.Arg201Cys) variant is classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg201 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15126527, 27506760). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GNAS function (PMID: 2549426). 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 expected to disrupt GNAS protein function. ClinVar contains an entry for this variant (Variation ID: 15933). This missense change has been observed in individual(s) with McCune-Albright syndrome, as a somatic mosaic variant (PMID: 16543670, 17873334, 20197676, 27506760). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the GNAS protein (p.Arg201Cys).
Citations for somatic classification of this variant
Help| There are no citations for somatic 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 rs11554273 ...
HelpThese 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 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.