VCV000015953.6 - ClinVar

NM_000516.7(GNAS):c.344C>T (p.Pro115Leu)

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.

(5)

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

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.344C>T (p.Pro115Leu)

Variation ID: 15953 Accession: VCV000015953.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.32 20: 58903703 (GRCh38) [ NCBI UCSC ] 20: 57478758 (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	Aug 22, 2016	Feb 14, 2024	Dec 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000516.7:c.344C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000507.1:p.Pro115Leu	missense
NM_016592.5:c.*250C>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.2273C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_536350.2:p.Pro758Leu	missense
NM_001077488.5:c.347C>T	NP_001070956.1:p.Pro116Leu	missense
NM_001077489.4:c.299C>T	NP_001070957.1:p.Pro100Leu	missense
NM_001077490.3:c.*205C>T		3 prime UTR
NM_001309840.2:c.167C>T	NP_001296769.1:p.Pro56Leu	missense
NM_001309861.2:c.167C>T	NP_001296790.1:p.Pro56Leu	missense
NM_080426.4:c.302C>T	NP_536351.1:p.Pro101Leu	missense
NC_000020.11:g.58903703C>T
NC_000020.10:g.57478758C>T
NG_016194.2:g.68964C>T

... more HGVS ... less HGVS

Protein change

P115L, P100L, P101L, P116L, P758L, P56L

Other names

Canonical SPDI

NC_000020.11:58903702:C:T

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

ClinGen: CA126104 OMIM: 139320.0029 dbSNP: rs137854539 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	949	1105

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.
Pseudohypoparathyroidism	Likely pathogenic (2)	criteria provided, single submitter	Jan 29, 2019	RCV000017323.26
Pseudopseudohypoparathyroidism	Pathogenic (1)	no assertion criteria provided	Oct 1, 2001	RCV000017322.28
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 16, 2022	RCV002243646.4

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.
Likely pathogenic (Apr 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002513028.2 First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is … (more) Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12621129, 11600516, 16789628, 24850831, 21274345, 15070926, 31886927) (less)
Likely pathogenic (Jan 29, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pseudohypoparathyroidism type I A (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Undiagnosed Diseases Network, NIH Accession: SCV000926990.1 First in ClinVar: Jul 21, 2019 Last updated: Jul 21, 2019	Number of individuals with the variant: 1 Clinical Features: Trigonocephaly (present) , Tracheomalacia (present) , Preeclampsia (present) , Strabismus (present) , Short stature (present) , Sagittal craniosynostosis (present) , Premature birth following premature rupture … (more) Trigonocephaly (present) , Tracheomalacia (present) , Preeclampsia (present) , Strabismus (present) , Short stature (present) , Sagittal craniosynostosis (present) , Premature birth following premature rupture of fetal membranes (present) , Premature birth (present) , Preeclampsia (present) , Poor suck (present) , Neonatal respiratory distress (present) , Metopic synostosis (present) , Intrauterine growth retardation (present) , Intellectual disability, borderline (present) , Hypothyroidism (present) , Hypophosphatemia (present) , Hypocalcemia (present) , Hyperparathyroidism (present) , Elevated circulating parathyroid hormone level (present) , Delayed fine motor development (present) , Decreased fetal movement (present) , Breech presentation (present) , Brachydactyly (present) , Attention deficit hyperactivity disorder (present) , Asthma (present) , Amblyopia (present) (less) Age: 0-9 years Sex: male Ethnicity/Population group: White Tissue: blood
Pathogenic (Dec 16, 2022)	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: SCV004298106.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 21274345‚ 28296742‚ 29059381‚ 11600516‚ 23884777 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro115 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.Pro115 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21274345, 28296742, 29059381). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 15953). This variant is also known as p.Pro116Leu. This missense change has been observed in individuals with pseudohypoparathyroidism type 1a (PMID: 11600516, 23884777). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 115 of the GNAS protein (p.Pro115Leu). (less)
Pathogenic (Oct 01, 2001)	no assertion criteria provided Method: literature only	PSEUDOHYPOPARATHYROIDISM, TYPE IA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037595.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016	Publications: PubMed (1) PubMed: 11600516 Comment on evidence: In a woman with PPHP (612463), Ahrens et al. (2001) identified a C-to-T transition in exon 5 of the GNAS gene, resulting in a pro115-to-leu … (more) In a woman with PPHP (612463), Ahrens et al. (2001) identified a C-to-T transition in exon 5 of the GNAS gene, resulting in a pro115-to-leu (P115L) substitution. Her son, who had the same mutation, had PHP Ia (103580). (less)
Pathogenic (Oct 01, 2001)	no assertion criteria provided Method: literature only	PSEUDOPSEUDOHYPOPARATHYROIDISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037594.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016	Publications: PubMed (1) PubMed: 11600516 Comment on evidence: In a woman with PPHP (612463), Ahrens et al. (2001) identified a C-to-T transition in exon 5 of the GNAS gene, resulting in a pro115-to-leu … (more) In a woman with PPHP (612463), Ahrens et al. (2001) identified a C-to-T transition in exon 5 of the GNAS gene, resulting in a pro115-to-leu (P115L) substitution. Her son, who had the same mutation, had PHP Ia (103580). (less)

Comment:

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12621129, 11600516, 16789628, 24850831, 21274345, 15070926, 31886927)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro115 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21274345, 28296742, 29059381). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 15953). This variant is also known as p.Pro116Leu. This missense change has been observed in individuals with pseudohypoparathyroidism type 1a (PMID: 11600516, 23884777). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 115 of the GNAS protein (p.Pro115Leu).

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

Title	Author	Journal	Year	Link
Ossifications in Albright Hereditary Osteodystrophy: Role of Genotype, Inheritance, Sex, Age, Hormonal Status, and BMI.	Salemi P	The Journal of clinical endocrinology and metabolism	2018	PMID: 29059381
Pseudohypoparathyroidism with basal ganglia calcification: A case report of rare cause of reversible parkinsonism.	Song CY	Medicine	2017	PMID: 28296742
Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development.	Richard N	The Journal of clinical endocrinology and metabolism	2013	PMID: 23884777
Long-term follow-up of a pseudohypoparathyroidism type 1A patient with missense mutation (Pro115Ser) in exon 5.	Savaş Erdeve Ş	Journal of clinical research in pediatric endocrinology	2010	PMID: 21274345
Analysis of the GNAS1 gene in Albright's hereditary osteodystrophy.	Ahrens W	The Journal of clinical endocrinology and metabolism	2001	PMID: 11600516

Text-mined citations for rs137854539 ...

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_000516.7(GNAS):c.344C>T (p.Pro115Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137854539 ...