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NM_000516.7(GNAS):c.691C>T (p.Arg231Cys) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Feb 3, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003336225.1

Allele description [Variation Report for NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)]

NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)

Gene:
GNAS:GNAS complex locus [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20q13.32
Genomic location:
Preferred name:
NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)
HGVS:
  • NC_000020.11:g.58909552C>T
  • NG_016194.2:g.74813C>T
  • NM_000516.7:c.691C>TMANE SELECT
  • NM_001077488.5:c.694C>T
  • NM_001077489.4:c.646C>T
  • NM_001077490.3:c.*552C>T
  • NM_001309840.2:c.514C>T
  • NM_001309861.2:c.514C>T
  • NM_016592.5:c.*597C>T
  • NM_080425.4:c.2620C>T
  • NM_080426.4:c.649C>T
  • NP_000507.1:p.Arg231Cys
  • NP_000507.1:p.Arg231Cys
  • NP_001070956.1:p.Arg232Cys
  • NP_001070957.1:p.Arg216Cys
  • NP_001296769.1:p.Arg172Cys
  • NP_001296790.1:p.Arg172Cys
  • NP_536350.2:p.Arg874Cys
  • NP_536351.1:p.Arg217Cys
  • NC_000020.10:g.57484607C>T
  • NC_000020.10:g.57484607C>T
  • NM_000516.4:c.691C>T
  • NM_000516.5:c.691C>T
  • NM_000516.6:c.691C>T
Protein change:
R172C
Links:
dbSNP: rs1601162438
NCBI 1000 Genomes Browser:
rs1601162438
Molecular consequence:
  • NM_001077490.3:c.*552C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_016592.5:c.*597C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000516.7:c.691C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077488.5:c.694C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077489.4:c.646C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001309840.2:c.514C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001309861.2:c.514C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080425.4:c.2620C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080426.4:c.649C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Pseudohypoparathyroidism type 1C (PHP1C)
Synonyms:
PSEUDOHYPOPARATHYROIDISM, TYPE IC; PHP IC
Identifiers:
MONDO: MONDO:0012911; MedGen: C2932716; Orphanet: 79444; OMIM: 612462
Name:
Pseudohypoparathyroidism type 1B (PHP1B)
Synonyms:
PHP IB; Pseudohypoparathyroidism Type IB
Identifiers:
MONDO: MONDO:0011301; MedGen: C1864100; Orphanet: 94089; OMIM: 603233
Name:
Pseudopseudohypoparathyroidism (PPHP)
Synonyms:
Albright hereditary osteodystrophy without multiple hormone resistance
Identifiers:
MONDO: MONDO:0012912; MedGen: C0033835; Orphanet: 79445; OMIM: 612463
Name:
Pseudohypoparathyroidism type I A (PHP1A)
Synonyms:
PHP IA; Pseudohypoparathyroidism type 1A; Albright hereditary osteodystrophy with multiple hormone resistance; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007078; MedGen: C3494506; OMIM: 103580

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004046480New York Genome Center
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Likely pathogenic
(Feb 3, 2023) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From New York Genome Center, SCV004046480.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.691C>T, p.(Arg231Cys) variant identified in the GNAS gene substitutes a well conserved Arginine for Cysteine at amino acid 231/395 (exon 9/13). This variant is absent from population databases. (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be damaging to the function of the canonical protein (REVEL: 0.857). The c.691C>T, p.(Arg231Cys) is reported in ClinVar in Pathogenic/Likely Pathogenic (VarID:816910; two stars, 7 submissions, no conflicts), and a different amino acid change at the same amino acid is also reported as Pathogenic (p.Arg231His; VarID:15946). This variant has been reported in individuals in the literature with pseudohypoparathyroidism or pseudopseudohypoparathyroidism [PMID:11600516, 25044890], and in an infant with Albright hereditary osteodystrophy [PMID: 30349702]. Given its absence in population databases, in silico prediction of a damaging effect on protein function, and observation in several individuals in the literature, the c.691C>T, p.(Arg231Cys) variant identified in the GNAS gene is reported as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Oct 20, 2024