PTEN c.398T>A, p.Val133Glu
NM_000314.8:c.398T>A
Likely Pathogenic
p.V133E (c.398T>A) is classified as Likely Pathogenic based on two Moderate criteria (PS3_moderate functional evidence and PM5 novel pathogenic‐residue missense) plus multiple Supporting criteria (PM2 absent from population, PP2 gene‐specific missense context, PP3 computational predictions, PP5 ClinVar report).
ACMG/AMP Criteria Applied
PS3
PM2
PM5
PP2
PP3
PP5
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.398T>A
Protein Change
V133E
Location
Exon 5
(Exon 5 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 133: V133I
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.398T>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Likely Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This variant is classified as Likely pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change; This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). Additional information: Variant is predicted to result in a missense amino acid change from valine to glutamic acid; This variant is heterozygous; This gene is associated with autosomal dominant disease; This variant has no previous evidence of pathogenicity; No published segregation evidence has been identified for this variant; No published functional evidence has been identified for this variant; Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. p.(Val133Leu) has been classified as a VUS and p.(Val133Ile) has been classified as both pathogenic and VUS by clinical laboratories (ClinVar); Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with PTEN-related disease (OMIM). Loss of function is the mechanism for null variants while missense variants have been demonstrated to exert either a loss of function or dominant-negative mechanism (PMID: 20301661); Variants in this gene are known to have variable expressivity. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (PMID: 20301661).
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 133: V133I
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.99
0.99
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.78
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: it is a missense change (c.398T>A; p.V133E) not predicted to cause loss‐of‐function under the PTEN PVS1 decision tree. Therefore, this criterion is not applied because the variant does not meet PVS1 requirements.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS1 is: "Strong Strength: Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant." The evidence for this variant shows: p.V133E is novel with no identical amino acid change previously reported as pathogenic. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS2 is: "Very Strong Strength: Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." The evidence for this variant shows: no confirmed de novo observations. Therefore, PS2 is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing the PS3_Moderate finding is: "Phosphatase activity score -2.0533 < threshold -1.11 per Mighell et al. 2018, PMID: 29706350." The evidence for this variant shows: the functional score of -2.0533 meets the PTEN-specific threshold for moderate functional impact. Therefore, PS3 is applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS4 is: "Moderate Strength: Moderate Probands with specificity score of 2-3.5 (see text)." The evidence for this variant shows: no case-level proband data available to calculate specificity score. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM1 is: "Moderate Strength: Moderate Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130 (NP_000305.3)." The evidence for this variant shows: p.V133E resides at codon 133, outside the defined catalytic motifs. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines the rule for PM2 is: "Supporting Strength: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%)." The evidence for this variant shows: the variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM3 is: "Moderate Strength: Moderate For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PTEN-related disease is haploinsufficient and no trans recessive data applies. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM4 is: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: p.V133E is a missense change without protein length alteration. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines the rule for PM5 is: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant." The evidence for this variant shows: residue V133 has previously observed pathogenic missense changes. Therefore, PM5 is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM6 is: "Moderate Strength: Moderate Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history." The evidence for this variant shows: no presumed de novo information. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PP1 is: "Supporting Strength: Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed." The evidence for this variant shows: no segregation data available. Therefore, PP1 is not applied.
PP2
PP2 (Supporting)
According to standard ACMG guidelines the rule for PP2 is: "Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: PTEN is intolerant to benign missense and missense is a known disease mechanism. Therefore, PP2 is applied at Supporting strength.
PP3
PP3 (Supporting)
According to VCEP guidelines the rule for PP3 is: "Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak Missense variants: REVEL score > 0.7." The evidence for this variant shows: REVEL score = 0.99 (>0.7) and multiple tools predict deleterious. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP4 is: "Supporting Phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype or family history details. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines the rule for PP5 is: "Supporting Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar lists this variant as Likely Pathogenic by one clinical laboratory. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BA1 is: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency = 0% in gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS1 is: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows: allele frequency = 0% in gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS2 is: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual..." The evidence for this variant shows: no homozygous observations in unaffected individuals. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS3 is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function..." The evidence for this variant shows: functional score indicates damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS4 is: "Strong Strength: Strong Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP1 is: "Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: PTEN disease mechanism includes both truncating and missense variants. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP2 is: "Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant..." The evidence for this variant shows: no trans observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP3 is: "Supporting In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a missense change. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP4 is: "Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Missense variants: REVEL scores < 0.5." The evidence for this variant shows: REVEL = 0.99 and other tools predict deleterious. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP5 is: "Supporting Strength: Supporting Variant found in a case with an alternate molecular basis for disease..." The evidence for this variant shows: no alternate molecular basis reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP6 is: "Supporting Reputable source reports variant as benign, but evidence is not available." The evidence for this variant shows: no reputable benign report. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP7 is: "Supporting Strength: Supporting A synonymous or intronic variant at or beyond +7/-21 with no splicing impact." The evidence for this variant shows: it is a missense change. Therefore, BP7 is not applied.