The RHOA NM_001664.4:c.50G>T (NP_001655.1:p.(Gly17Val)) missense variant has previously been reported in somatic cancers (COSMIC; COSV69041529, n = 313 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Independent biochemical and cellular assays showed RHOA p.Gly17Val lost GTPase activity and altered signaling versus wild-type controls. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.RHOA encodes a small GTPase that acts as a molecular switch to regulate the actin cytoskeleton, cell shape, attachment, movement, and signaling. It is involved in cancer development and spread, but its effects can vary by tumor type because both increased activity and loss or inactivation of RHOA have been associated with cancer. No established non-cancer disease association is described here.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: independent biochemical and cellular assays showed RHOA p.Gly17Val lost GTPase activity and altered signaling versus wild-type controls.
Met: residue G17 is reported in a statistically significant Cancer Hotspots hotspot, and the variant is absent from gnomAD v2.1 and v4.1.
Met at Supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer datasets, satisfying the <=0.0001 PM2 frequency threshold.
Met, strong: REVEL 0.952 meets the generic PP3 strong threshold of >=0.932 for missense variants.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 strong, PM1 moderate, PM2 supporting, and PP3 strong satisfy the generic ACMG/AMP fallback combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.952. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: no assertion criteria provided.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV69041529, n = 313 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 7 not met · 13 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For RHOA p.Gly17Val, the available evidence supports the generic PM1 hotspot route, while PS1 and PM5 lack the required verified pathogenic comparator evidence and PP2/BP1 lack their required gene-level mechanism data.
No germline proband, parental testing, pedigree, segregation, or non-segregation evidence was documented for NM_001664.4:c.50G>T (RHOA p.Gly17Val).
The available variant-specific publications describe somatic lymphoma findings and do not establish PS2, PM6, PP1, or BS4 evidence for this germline segregation/de novo assessment.
PS3 is met at strong strength because independent studies of the exact RHOA p.Gly17Val variant used orthogonal biochemical and cellular assays with wild-type comparisons and consistently demonstrated impaired function.
BS3 is not met because the available functional evidence is damaging rather than benign.
This group evaluated only PP3 and BP4. The variant is missense, so both criteria use the REVEL path exclusively; the same REVEL prediction is not double-counted across criteria, and SpliceAI is not used for either missense decision.
No criteria match.
PS3 is met at strong strength for NM_001664.4:c.50G>T (RHOA p.Gly17Val). Two independent full-text studies directly tested the exact variant against wild-type controls using orthogonal biochemical and cellular assays. In PMID:24413734, Gly17Val failed to bind the active-RHOA effector rhotekin, was resistant to GEF-stimulated GTP loading, altered cellular morphology and F-actin organization, and showed altered interaction with ARHGEF1. In PMID:24584070, Gly17Val failed the RHOA GTPase activity assay and increased proliferation, invasion, and AKT phosphorylation relative to wild-type RHOA. These concordant results demonstrate loss of normal RHOA function and a damaging biological effect. The evidence is strong under the generic ACMG/AMP functional definition, although the studies are research assays rather than explicitly validated clinical diagnostic-laboratory tests.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
RHOA p.Gly17Val lies at residue G17, which the Cancer Hotspots result identifies as a statistically significant hotspot. The variant is absent from gnomAD v2.1 and v4.1, providing no observed population benign variation for this variant. Under the generic rule, the documented mutational-hotspot route supports PM1; no VCEP domain table or gene-specific critical-domain restriction applies.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is met at Supporting strength. NM_001664.4:c.50G>T (RHOA p.Gly17Val) was absent from gnomAD v2.1 and gnomAD v4.1, and was also absent from the available gnomAD v2.1 non-cancer and v3.1 non-cancer records. This is below the supplied generic PM2 threshold of <=0.0001 and supports absence from reference controls; the result is not being used to infer any other criterion.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a missense substitution, NM_001664.4:c.50G>T (NP_001655.1:p.Gly17Val), so the generic PP3 missense path applies and REVEL is the applicable predictor; SpliceAI is not used for this path. REVEL is 0.952, meeting the supplied generic ClinGen SVI strong PP3 threshold of >= 0.932 (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established, and the SpliceAI score is not counted for a missense PP3 decision.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The exact ClinVar record is Pathogenic but has no assertion criteria, zero review stars, no expert-panel submission, and no usable expert-panel classification. The available literature is not an exact-variant ClinVar expert-panel assertion that can trigger PP5 under the required generic rule. Therefore PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. NM_001664.4:c.50G>T (RHOA p.Gly17Val) was absent from gnomAD v2.1 and gnomAD v4.1, so no filtering allele frequency or grpmax FAF is available and the >=0.05 threshold is not reached. The non-cancer gnomAD v2.1 and v3.1 records were also absent. There is no population-frequency basis for a stand-alone benign call.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. The variant was absent from gnomAD v2.1 and gnomAD v4.1, as well as the available non-cancer gnomAD v2.1 and v3.1 records; therefore no filtering allele frequency or grpmax FAF exceeds the generic 0.01 threshold. Because no elevated population frequency is present, the reduced-penetrance, prevalence, allelic-heterogeneity, and founder-allele caveats do not create a BS1 path here.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS3 is not met. The available variant-specific functional studies do not show no damaging effect on RHOA function or splicing; instead, they report impaired GTPase activity, altered effector or GEF interactions, and abnormal cellular phenotypes for p.Gly17Val. No well-established benign functional or splicing study was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense substitution, so BP4 must be assessed through the generic REVEL path only; SpliceAI cannot substitute for a gray-zone or non-benign REVEL result in a missense variant. REVEL is 0.952, which exceeds the most permissive supplied BP4 supporting threshold of <= 0.29 and therefore does not support no impact. BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The exact variant is reported in lymphoma cases and some papers report co-occurring TET2 mutations, including the statement that all p.Gly17Val-positive AITL cases also had TET2 mutations. However, the evidence does not establish that an alternate molecular basis independently explains the disease in a case carrying this variant; co-occurrence in somatic tumors is not sufficient to apply BP5. Therefore BP5 is not met.
Variant found in a case with an alternate molecular basis for disease.
No exact-variant ClinVar expert-panel classification of Benign or Likely benign is present. ClinVar contains a zero-star Pathogenic research submission and an Oncogenic single-submitter submission, neither of which can trigger BP6. Therefore BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is NP_001655.1:p.(Gly17Val), and the reviewed literature confirms this exact amino-acid change, but the available records do not establish a previously pathogenic Gly17Val caused by a different nucleotide change. The exact same c.50G>T event is not PS1 evidence by itself. The variant is a missense substitution and SpliceAI reports a maximum delta score of 0.002, so the protein-level comparison is not confounded by a predicted splice effect.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
No proband-level de novo observation with confirmed maternity and paternity, a disease-consistent phenotype, and no family history was documented. The available variant-specific publications concern somatic lymphoma rather than germline de novo testing, so PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The PS4 rule requires a significant increase in affected individuals compared with controls, with RR or OR >5.0 and a confidence interval that excludes 1.0. The reviewed papers verify that the exact RHOA p.Gly17Val variant occurs in AITL and other peripheral T-cell lymphoma cohorts, including 24/45 AITL in PMID:24584070 and 22/35 AITL plus 8/44 PTCL-NOS in PMID:24413734. However, these reports do not provide unaffected or matched-population control counts for the exact variant, so an eligible case-control OR/RR and 95% CI cannot be calculated. The PS4-triaged papers PMID:22918138 and PMID:34131312 were checked in full text and do not mention RHOA or this variant; therefore they provide no case-control evidence. No threshold inequality can be evaluated because the required case-control estimate and confidence interval are unavailable.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 cannot be assessed because the available evidence concerns a somatic RHOA p.Gly17Val variant in lymphoma rather than an established recessive germline disorder. No affected-proband observation documents this variant with a pathogenic allele in trans, and no parental or offspring testing establishes phase. The cited tumor studies describe heterozygous somatic observations but do not provide cis/trans relationships to a pathogenic variant.
For recessive disorders, detected in trans with a pathogenic variant
The queried variant changes Gly17 to Val. The reviewed literature reports another missense change at Gly17, p.Gly17Glu, but does not establish that comparator as pathogenic under the governing ACMG/AMP rule. The available ClinVar record is a somatic single-submitter record without usable assertion criteria, so it cannot supply the required pathogenic determination for PM5.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
No proband-level assumed de novo observation was documented. The available variant-specific publications concern somatic lymphoma and do not establish a germline event or parental testing status, so PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, familial variant testing, or meioses were documented. Therefore, co-segregation and any possible strengthening based on increasing segregation data cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
RHOA is a missense variant in a gene with documented disease-relevant missense observations, but the evidence bundle does not provide the two required gene-level facts: a low rate of benign missense variation and missense variants as a common mechanism of disease. Variant absence from gnomAD and recurrent somatic cancer observations cannot substitute for those unspecified PP2 requirements.
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 case materials do not provide an individual patient's phenotype or family history for this variant, and the available publications describe somatic lymphoma cohorts rather than a highly specific phenotype in an individual with a single genetic etiology. The criterion therefore cannot be assessed from the supplied evidence.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. The population records document absence from gnomAD but do not provide an observed healthy adult carrier or homozygote/hemizygote observation for this variant. No reliable disease inheritance, expected age of onset, or penetrance specification is available in the governing generic evidence, so the required healthy-adult observation cannot be established.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No affected family members with variant testing were documented, so lack of segregation cannot be evaluated. The available somatic lymphoma reports do not constitute affected-family non-segregation evidence; phenocopy and multiple-variant caveats therefore cannot be assessed.
Lack of segregation in affected members of a family.
The variant is missense, so BP1's variant-type scope is applicable, but the available evidence does not establish that RHOA is a gene for which disease is caused primarily by truncating variants. The reviewed records describe recurrent somatic missense RHOA variants and do not provide a sufficiently characterized disease-variant spectrum to support or refute the primarily truncating requirement.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed because the available evidence does not establish a fully penetrant dominant germline RHOA disorder, a pathogenic variant in trans, or a pathogenic variant in cis. The available studies concern somatic lymphoma samples and report no phase testing or affected-proband family observations; therefore they cannot support either BP2 pathway.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001664.4:c.50G>T in RHOA is a missense substitution predicted to produce NP_001655.1:p.(Gly17Val). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for RHOA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001664.4:c.50G>T in RHOA is a missense substitution predicted to produce NP_001655.1:p.(Gly17Val). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for RHOA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001664.4:c.50G>T in RHOA is a missense substitution predicted to produce NP_001655.1:p.(Gly17Val). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for RHOA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001664.4:c.50G>T in RHOA is a missense substitution predicted to produce NP_001655.1:p.(Gly17Val). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for RHOA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in RHOA, mapped onto the exon structure of NM_001664.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_001664.4:c.50G>T (NP_001655.1:p.Gly17Val), so the generic PP3 missense path applies and REVEL is the applicable predictor; SpliceAI is not used for this path. REVEL is 0.952, meeting the supplied generic ClinGen SVI strong PP3 threshold of >= 0.932 (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established, and the SpliceAI score is not counted for a missense PP3 decision.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The variant is a missense substitution, so BP4 must be assessed through the generic REVEL path only; SpliceAI cannot substitute for a gray-zone or non-benign REVEL result in a missense variant. REVEL is 0.952, which exceeds the most permissive supplied BP4 supporting threshold of <= 0.29 and therefore does not support no impact. BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001664.4:c.50G>T in RHOA is a missense substitution predicted to produce NP_001655.1:p.(Gly17Val). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for RHOA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.952. BayesDel score = 0.569381.
6 paper records listed. 2 cited in the classification.
These results were confirmed and extended by deep sequencing analysis of 125 PTCL DNAs, which showed the presence of the recurrent RHOA p.Gly17V mutation and detected several additional RHOA mutations (p.Cys16Arg, p.Thr19Ile, p.Gly17Glu and p.Asp120Tyr) present in a single case each (Fig. 1a and Supplementary Table 5).
Location Results, paragraphs describing RHOA mutation discovery and prevalence; Fig. 1 and Supplementary Table 5
Context Matched tumor-normal whole-exome sequencing, targeted deep resequencing of 125 PTCL DNAs, allele-specific PCR in PTCL cohorts, and functional RHOA assays.
Further examination of the RHOA mutation encoding p.Gly17Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma.
Location Abstract and Results, pages 372–375; Fig. 4
Context Whole-exome and transcriptome sequencing, Sanger validation in lymphoma cohorts, RHOA GTPase activity, proliferation and invasion assays, and structural modeling.
Here we report somatic RHOA mutations encoding a p.Gly17Val alteration in 68% of AITL samples. Remarkably, all cases with the mutation encoding p.Gly17Val also had TET2 mutations.
Abstract
One of the complexities is the assignment of pathogenicity of variants.
Clinical Utility, page 529
Duplications and deletions below the detection level according to probe coverage and performance, single-nucleotide variants (SNVs) or insertions/deletions (indels) not covered by the platform, gene expression, or epigenetic modifications.
Limitations of CMA
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 2681515)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.952. BayesDel score = 0.569381.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV69041529, n = 313 times).
This variant lies in a statistically significant hotspot.