rs786204929
Variant summary
Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.385G>A(p.Gly129Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G129E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 27 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.385G>A | p.Gly129Arg | missense_variant | 5/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.904G>A | p.Gly302Arg | missense_variant | 6/10 | ||
PTEN | NM_001304718.2 | c.-366G>A | 5_prime_UTR_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.385G>A | p.Gly129Arg | missense_variant | 5/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461698Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727150
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly129 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21659347, 30327747). 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 PTEN function (PMID: 9256433, 17928923, 25527629). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 189484). This missense change has been observed in individual(s) with Cowden syndrome (PMID: 22469695). 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 glycine with arginine at codon 129 of the PTEN protein (p.Gly129Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cowden syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 27, 2023 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302, 25527629]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22469695, 24766807]. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2019 | Published functional studies demonstrate a damaging effect: decreased phosphatase activity (Furnari 1998, Spinelli 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29142193, 28497778, 9823298, 25527629, 11274365, 15659546, 15988030, 25714556, 27481051, 22469695, 31085179, 33509259) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 14, 2019 | The p.G129R variant (also known as c.385G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 385. The glycine at codon 129 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in an individual with features of PTEN hamaratoma tumor syndrome (PHTS), including Lhermitte-Duclos disease and macrocephaly (Elia M et al. Brain Dev., 2012 Nov;34:873-6). Functional analyses of p.G129R have demonstrated PTEN protein stability similar to wild-type; however, it demonstrated a complete inability of the G129R mutated protein to suppress AKT signaling, a key role of PTEN (Spinelli L et al. J. Med. Genet., 2015 Feb;52:128-34). In addition, two mutations at the same codon, p.G129E and p.G129V have been detected in individuals with features of PHTS (Liaw D et al. Nat. Genet. 1997 May;16:64-7; Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Ngeow J et al. Gastroenterology. 2013 Jun; 144(7):1402-9, 1409.e1-5). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at