No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.DLST encodes a mitochondrial protein that forms part of the 2-oxoglutarate dehydrogenase complex, which helps convert 2-oxoglutarate into succinyl-CoA and carbon dioxide as part of cellular energy production. It has been associated with disease through disruption of mitochondrial energy metabolism. No established role in cancer is known.
The recorded framework is Not recorded. 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 at supporting strength: gnomAD v4.1 allele frequency is 1.24e-06, below the <=0.0001 PM2 threshold, with zero homozygotes.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 (supporting) is the only met criterion and does not meet generic ACMG/AMP thresholds for a definitive classification.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 2 / 1,611,108 alleles. Recorded AF 1.24138e-06. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.519. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 7 not met · 16 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No DLST-specific VCEP or gene-specific framework was identified; generic ACMG/AMP criteria were used only where applicable.
The available case data contain no individual phenotype, phenotype-specific literature, case-control enrichment analysis, alternate molecular diagnosis, or exact-variant ClinVar expert-panel assertion.
No applicable DLST-specific VCEP or gene-specific framework was identified; generic ACMG/AMP and supplied ClinGen SVI population defaults were applied.
The population evidence supports PM2 at supporting strength only; the observed gnomAD frequency is far below BA1 and BS1 thresholds, and no healthy homozygote observation supports BS2.
No criteria match.
PM2 at supporting strength is met. No applicable DLST-specific VCEP or gene framework was identified, so the supplied generic ClinGen SVI recommendation is used: PM2 supporting when the population allele frequency is <=0.0001 (PMID:25741868). The variant is absent from gnomAD v2.1 and present only twice in gnomAD v4.1, with an all-comers allele frequency of 1.2413817074957111e-06 (2/1611108), zero homozygotes, and a highest subpopulation frequency of 1.6953319036034279e-06. The reported non-cancer subsets are also absent, but they are not the governing source because no specification requires them; the default all-comers gnomAD v2.1/v4.1 entries therefore control.
Generic ClinGen SVI PM2: population allele frequency <=0.0001 supports PM2; apply at supporting strength.
The variant is a missense substitution, NM_001933.5:c.236C>T (p.Ala79Val), so PP3 must be assessed through the REVEL path only. REVEL is 0.519, below the generic ClinGen SVI supporting threshold of 0.644; therefore PP3 is not met. The SpliceAI max delta of 0.08 was not used because splice predictions are not evidence for missense PP3 under the selected pathway.
PP5 is restricted here to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion. The exact variant is absent from ClinVar, with no variation ID, classification, review status, or expert-panel assertion; PP5 is therefore not met.
PP5 applies only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
BA1 is not met. Under the generic ACMG/AMP default, the stand-alone benign threshold is allele frequency >=0.05 (ACMG/AMP 2015, PMID:25741868). The variant's gnomAD v4.1 all-comers allele frequency is 1.2413817074957111e-06 (2/1611108 alleles), with the highest reported subpopulation frequency 1.6953319036034279e-06 in European non-Finnish individuals; both are far below 0.05. No applicable DLST-specific VCEP specification was identified, so the default all-comers dataset is used; the non-cancer subsets do not alter this assessment.
Generic ACMG/AMP BA1: allele frequency >=0.05.
BS1 is not met. Under the generic ACMG/AMP default, the strong benign threshold is allele frequency >=0.01, with per-gene derivation preferred (Whiffin et al., PMID:28518168). The gnomAD v4.1 all-comers allele frequency is 1.2413817074957111e-06 (2/1611108 alleles), and the highest reported subpopulation frequency is 1.6953319036034279e-06; neither approaches 0.01. No applicable DLST-specific VCEP specification was identified, so the default all-comers dataset is used.
Generic ACMG/AMP BS1: allele frequency >=0.01; per-gene derivation preferred.
BS2 is not met. gnomAD v4.1 reports zero homozygotes among 2 observed variant alleles, and gnomAD v2.1 reports the variant as absent. These data do not provide the required observation of the variant in healthy adults, particularly healthy homozygous individuals where relevant to the disease mechanism; absence of homozygotes is not positive BS2 evidence. No applicable DLST-specific VCEP specification was identified.
Generic ACMG/AMP BS2 requires observation in healthy adults, with homozygote observation considered when relevant; absence of homozygotes does not meet BS2.
The variant is a missense substitution, NM_001933.5:c.236C>T (p.Ala79Val), so BP4 must be assessed through the REVEL path only. REVEL is 0.519, above the generic ClinGen SVI supporting BP4 threshold of 0.29; therefore BP4 is not met. The SpliceAI max delta of 0.08 was not used because a splice prediction cannot establish BP4 for a missense variant under the selected pathway.
BP6 is restricted here to an exact-variant ClinVar expert-panel Benign or Likely benign assertion. The exact variant is absent from ClinVar, with no variation ID, classification, review status, or expert-panel assertion; BP6 is therefore not met.
BP6 applies only to an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
PS1 requires a previously established pathogenic or likely pathogenic missense substitution producing the same amino-acid change. The supplied evidence contains no ClinVar record for this variant, no literature PMIDs, and no documented pathogenic same-amino-acid comparator; therefore PS1 cannot be assessed from the available evidence.
PS1: same amino-acid change as an established pathogenic variant; generic ACMG/AMP fallback applies because no DLST-specific specification was available.
PS2 requires evidence that the variant arose de novo in an affected proband, with confirmed maternity and paternity and preferably phenotype consistency. The available case evidence identifies NM_001933.5:c.236C>T in DLST as a missense variant but provides no proband description, parental genotypes, trio testing results, maternity or paternity confirmation, or de novo observation. Therefore PS2 cannot be assessed.
Generic ACMG/AMP PS2: confirmed de novo occurrence in an affected individual requires maternity and paternity confirmation; strength depends on phenotype and confirmation quality.
No applicable DLST-specific VCEP specification was identified, so generic ACMG/AMP functional-evidence principles apply. The available case evidence contains no variant-specific functional assay, validated assay controls, quantitative result, or biologically relevant experiment for NM_001933.5:c.236C>T (NP_001924.2:p.Ala79Val). Therefore, a damaging functional effect cannot be established and PS3 is not assessed; the absence of functional evidence is not evidence against the variant.
No DLST-specific VCEP framework is available. The case evidence contains no affected-case series, control comparison, allele-count enrichment analysis, odds ratio, or other statistically significant case-control evidence for NM_001933.5:c.236C>T; therefore the PS4 requirement cannot be assessed.
Generic ACMG/AMP PS4: significantly increased prevalence of the variant in affected individuals compared with controls; no DLST-specific VCEP specification was identified.
PM1 requires a well-established critical functional domain or hotspot. No governing VCEP specification was available, vcep_materials.json contained no DLST domain table, and the supplied hotspot query found no statistically significant hotspot; a validated domain source for residue 79 is therefore missing.
PM1: variant lies in a well-established critical functional domain or hotspot; generic ACMG/AMP fallback applies only when the domain or hotspot is independently established.
No applicable DLST-specific VCEP or gene framework was identified, so the generic ACMG/AMP PM3 rule applies. The available case evidence does not document an affected individual with this variant in a confirmed biallelic or compound-heterozygous state, a pathogenic variant in trans, or informative parental phase. Therefore, PM3 cannot be assessed from the available evidence.
Generic ACMG/AMP PM3: evidence that the variant is observed in trans with a pathogenic variant in an affected individual with a recessive disorder, with strength determined by the number and quality of confirmed observations.
PM5 requires an independently established pathogenic missense change at the same residue, with strength determined by the applicable specification. The comparator artifact identified no same-residue candidates and explicitly could not confirm classic PM5 semantics, while ClinVar had no record; PM5 cannot be assigned.
PM5: novel missense change at an amino-acid residue where a different missense change is established as pathogenic; no applicable DLST-specific rule was available.
PM6 requires a presumed de novo variant in an affected individual when maternity and/or paternity is not confirmed. The available case evidence contains no affected proband phenotype, parental genotypes, family history, or report of a de novo event for NM_001933.5:c.236C>T in DLST. Without documentation of an apparently de novo occurrence, PM6 cannot be assessed.
Generic ACMG/AMP PM6: presumed de novo occurrence in an affected individual without confirmed maternity and/or paternity.
PP1 requires co-segregation of the variant with disease in affected family members, with strength informed by the number of informative meioses and phenotype specificity. The available case evidence contains no pedigree, affected or unaffected relatives, genotype-phenotype observations, informative meioses, or segregation statistics for NM_001933.5:c.236C>T in DLST. PP1 therefore cannot be assessed.
Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members; strength should reflect informative meioses and the specificity of the phenotype.
PP2 requires evidence that missense variants are a common disease mechanism for the gene and that benign missense variation is relatively uncommon. The available materials provide no validated DLST-specific missense-enrichment or benign-missense-rate assessment, so PP2 cannot be assigned.
PP2: missense variants are a common disease mechanism in the gene and benign missense variation is uncommon; generic fallback requires gene-level supporting data.
No DLST-specific VCEP framework is available. The evidence provides no individual phenotype, clinical diagnosis, or phenotype description for this variant, so the specificity of the phenotype for a DLST-related disorder cannot be evaluated under PP4.
Generic ACMG/AMP PP4: the patient's phenotype or family history is highly specific for a disease with a single genetic etiology; no DLST-specific VCEP specification was identified.
No applicable DLST-specific VCEP specification was identified, so generic ACMG/AMP functional-evidence principles apply. The available case evidence contains no variant-specific functional assay, validated assay controls, quantitative result, or biologically relevant experiment demonstrating preserved DLST function for NM_001933.5:c.236C>T (NP_001924.2:p.Ala79Val). Therefore, a benign functional effect cannot be established and BS3 is not assessed; the absence of functional evidence is not evidence for pathogenicity.
BS4 requires a lack of segregation in affected members of a family, with appropriate assessment of phenotype, age-related penetrance, and testing quality. The available case evidence contains no pedigree, affected relatives, family genotypes, clinical status, or non-segregation observation for NM_001933.5:c.236C>T in DLST. Absence of family data is not evidence against segregation, so BS4 cannot be assessed.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family, after accounting for phenotype definition, penetrance, age, and testing adequacy.
BP1 requires a well-established gene-specific pattern in which disease is caused predominantly by truncating or other non-missense variants and missense variation is not a recognized mechanism. The supplied materials do not establish that pattern for DLST, so BP1 cannot be assigned.
BP1: missense variants are not a common disease mechanism in the gene; generic fallback requires a well-established gene-specific mechanism pattern.
No applicable DLST-specific VCEP or gene framework was identified, so the generic ACMG/AMP BP2 rule applies. The available case evidence does not document this variant in cis with a pathogenic variant, in trans with a pathogenic variant in a recessive disorder, or in an affected individual carrying another established pathogenic explanation. Therefore, BP2 cannot be assessed from the available evidence.
Generic ACMG/AMP BP2: the variant is observed in trans with a pathogenic variant for a fully penetrant dominant gene or in cis with a pathogenic variant, or is present in an affected individual with another pathogenic variant that explains the phenotype.
No DLST-specific VCEP framework is available. The available evidence contains no documented alternate molecular basis that explains the individual's phenotype, and no individual phenotype is provided; BP5 cannot therefore be assessed rather than inferred from the absence of other findings.
Generic ACMG/AMP BP5: a pathogenic variant in an alternative gene explains the phenotype; no DLST-specific VCEP specification was identified.
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
deterministic_prefilter: requires_synonymous
Every interpreted variant in DLST, mapped onto the exon structure of NM_001933.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)2 / 1,179,710 | 1.7e-06 |
This variant is present in gnomAD v4.1 (AF= 1.24138e-06; MAF= 0.00012%, 2/1611108 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69533e-06; MAF= 0.00017%, 2/1179710 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_001933.5:c.236C>T (p.Ala79Val), so PP3 must be assessed through the REVEL path only. REVEL is 0.519, below the generic ClinGen SVI supporting threshold of 0.644; therefore PP3 is not met. The SpliceAI max delta of 0.08 was not used because splice predictions are not evidence for missense PP3 under the selected pathway.
The variant is a missense substitution, NM_001933.5:c.236C>T (p.Ala79Val), so BP4 must be assessed through the REVEL path only. REVEL is 0.519, above the generic ClinGen SVI supporting BP4 threshold of 0.29; therefore BP4 is not met. The SpliceAI max delta of 0.08 was not used because a splice prediction cannot establish BP4 for a missense variant under the selected pathway.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.519. BayesDel score = 0.235208.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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.
This variant is present in gnomAD v4.1 (AF= 1.24138e-06; MAF= 0.00012%, 2/1611108 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69533e-06; MAF= 0.00017%, 2/1179710 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.519. BayesDel score = 0.235208.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.