The c.2361+1G>A splice-site variant affects the canonical splice donor site of intron 5 and is thus predicted to be a loss of function mutation. It has been reported as a de novo heterozygous change in a patient with pseudopseudohypoparathyroidism (Wilson et al, 1997) and is absent from the ExAC and gnomAD population databases. Sanger sequencing of the parental samples was negative for the variant indicating that this variant likely represents a de novo change in the patient. However, low level parental mosaicism cannot be excluded. Based on the combined evidence, c.2361+1G>A is classified as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_000516.7(GNAS):c.432+1G>A
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000516.7(GNAS):c.432+1G>A
Variation ID: 446491 Accession: VCV000446491.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 20q13.32 20: 58903792 (GRCh38) [ NCBI UCSC ] 20: 57478847 (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 Dec 9, 2017 Feb 14, 2024 Sep 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000516.7:c.432+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_016592.5:c.*338+1G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_080425.4:c.2361+1G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000516.6:c.432+1G>A NM_001077488.5:c.435+1G>A splice donor NM_001077489.4:c.387+1G>A splice donor NM_001077490.3:c.*293+1G>A splice donor NM_001309840.2:c.255+1G>A splice donor NM_001309861.2:c.255+1G>A splice donor NM_001410912.1:c.336+1G>A splice donor NM_001410913.1:c.2316+1G>A splice donor NM_080426.4:c.390+1G>A splice donor NC_000020.11:g.58903792G>A NC_000020.10:g.57478847G>A NG_016194.2:g.69053G>A - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000020.11:58903791:G:A
-
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.
- -
- 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 (3) |
criteria provided, multiple submitters, no conflicts
|
May 8, 2023 | RCV000515760.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2023 | RCV001857879.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 29, 2016 | RCV000623168.2 |
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
(Dec 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudopseudohypoparathyroidism
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000623565.1
First in ClinVar: Dec 09, 2017 Last updated: Dec 09, 2017 |
Comment:
The c.2361+1G>A splice-site variant affects the canonical splice donor site of intron 5 and is thus predicted to be a loss of function mutation. It … (more)
The c.2361+1G>A splice-site variant affects the canonical splice donor site of intron 5 and is thus predicted to be a loss of function mutation. It has been reported as a de novo heterozygous change in a patient with pseudopseudohypoparathyroidism (Wilson et al, 1997) and is absent from the ExAC and gnomAD population databases. Sanger sequencing of the parental samples was negative for the variant indicating that this variant likely represents a de novo change in the patient. However, low level parental mosaicism cannot be excluded. Based on the combined evidence, c.2361+1G>A is classified as a pathogenic variant. (less)
Sex: male
|
|
|
Pathogenic
(Aug 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741652.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Short stature (present) , Skeletal dysplasia (present) , Pituitary adenoma (present) , Diplopia (present) , Amenorrhea (present) , Cranial hyperostosis (present) , Calcification of falx … (more)
Short stature (present) , Skeletal dysplasia (present) , Pituitary adenoma (present) , Diplopia (present) , Amenorrhea (present) , Cranial hyperostosis (present) , Calcification of falx cerebri (present) , Brachydactyly (present) , Irregular phalanges (present) , Osteoarthritis (present) , Hyperextensible hand joints (present) , Small hand (present) , Broad thumb (present) , Short 2nd finger (present) , Short hallux (present) , Brachymetatarsus 4 (present) , Pes planus (present) , Nail dysplasia (present) , Anorexia (present) , Self-injurious behavior (present) , Vertigo (present) , Blurred vision (present) , Menstrual irregularities (present) , Polycystic ovaries (present) , Hyperextensible skin (present) , Soft skin (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Dec 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002243970.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with pseudopseudohypoparathyroidism (PMID: 7853365). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 446491). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the GNAS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GNAS are known to be pathogenic (PMID: 11784876, 23281139, 23796510, 25802881). (less)
|
|
|
Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004031940.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a … (more)
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29072892, 23281139, 25525159, 23884777, 31624069, 30577886, 31019026, 31886927, 25802881, 7853365, 35296306) (less)
|
|
|
Pathogenic
(May 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudopseudohypoparathyroidism
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004041435.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Pseudopseudohypoparathyroidism
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000611855.2
First in ClinVar: Dec 09, 2017 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with pseudopseudohypoparathyroidism (PMID: 7853365). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 446491). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the GNAS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GNAS are known to be pathogenic (PMID: 11784876, 23281139, 23796510, 25802881).
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29072892, 23281139, 25525159, 23884777, 31624069, 30577886, 31019026, 31886927, 25802881, 7853365, 35296306)
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 c.2361+1G>A splice-site variant affects the canonical splice donor site of intron 5 and is thus predicted to be a loss of function mutation. It has been reported as a de novo heterozygous change in a patient with pseudopseudohypoparathyroidism (Wilson et al, 1997) and is absent from the ExAC and gnomAD population databases. Sanger sequencing of the parental samples was negative for the variant indicating that this variant likely represents a de novo change in the patient. However, low level parental mosaicism cannot be excluded. Based on the combined evidence, c.2361+1G>A is classified as a pathogenic variant.
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with pseudopseudohypoparathyroidism (PMID: 7853365). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 446491). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the GNAS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GNAS are known to be pathogenic (PMID: 11784876, 23281139, 23796510, 25802881).
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29072892, 23281139, 25525159, 23884777, 31624069, 30577886, 31019026, 31886927, 25802881, 7853365, 35296306)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Biallelic loss of GNAS in a patient with pediatric medulloblastoma. | Tokita MJ | Cold Spring Harbor molecular case studies | 2019 | PMID: 31624069 |
| A positive genotype-phenotype correlation in a large cohort of patients with Pseudohypoparathyroidism Type Ia and Pseudo-pseudohypoparathyroidism and 33 newly identified mutations in the GNAS gene. | Thiele S | Molecular genetics & genomic medicine | 2015 | PMID: 25802881 |
| Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series. | Elli FM | Bone | 2013 | PMID: 23796510 |
| Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations. | Elli FM | Human mutation | 2013 | PMID: 23281139 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Analysis of GNAS1 and overlapping transcripts identifies the parental origin of mutations in patients with sporadic Albright hereditary osteodystrophy and reveals a model system in which to observe the effects of splicing mutations on translated and untranslated messenger RNA. | Rickard SJ | American journal of human genetics | 2003 | PMID: 12624854 |
| Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. | Shore EM | The New England journal of medicine | 2002 | PMID: 11784876 |
| Parental origin of Gs alpha gene mutations in Albright's hereditary osteodystrophy. | Wilson LC | Journal of medical genetics | 1994 | PMID: 7853365 |
Text-mined citations for rs1555889131 ...
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 Sep 29, 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.