About SDHB
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SDHB c.172A>G, p.(Met58Val)
Classification
Uncertain significance
Variant description:
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen SDHB VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_003000.3:c.172A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting a low population frequency consistent with a rare pathogenic variant. PM2 at supporting level is applied per generic ACMG/AMP 2015 criteria for variants absent from large population databases.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Endocrine Tumor Predisposition Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SDHB Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions
5 Uncertain significance · 1 Uncertain Significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SDHB, a subunit of succinate dehydrogenase, is infrequently altered in cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen SDHB VCEP v1.0.0, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 20 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_003000.3:c.172A>G (p.Met58Val) is a missense variant in SDHB, a tumor suppressor gene associated with autosomal dominant hereditary pheochromocytoma-paraganglioma.
This variant is absent from gnomAD v2.1 and v4.1, supporting PM2 at supporting level per generic ACMG/AMP 2015 criteria.
Six clinical laboratories have submitted this variant to ClinVar, all classifying it as Uncertain Significance (ClinVar variation ID: 459138).
In silico predictions are indeterminate: SpliceAI predicts no splice impact (max delta 0.00) and BayesDel score is 0.338, which does not reach a pathogenic or benign threshold. REVEL score is unavailable.
No functional studies, case reports, segregation data, or de novo observations have been identified for this variant in the reviewed literature or curated databases.
No pathogenic missense variant at the same amino acid residue (Met58) was identified for PM5 comparison.
The ClinGen Endocrine Tumor Predisposition Expert Panel specifications for SDHB (version 1.0.0) were identified but contained no parsed criterion-level rules; classification adheres to generic ACMG/AMP 2015 framework.
With only PM2_Supporting met and no additional pathogenic or benign criteria satisfied, the variant remains a Variant of Uncertain Significance per ACMG/AMP 2015 combination rules (PMID:25741868).
No criteria match.
Met · 1
PM2 SupportingNM_003000.3:c.172A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting a low population frequency consistent with a rare pathogenic variant. PM2 at supporting level is applied per generic ACMG/AMP 2015 criteria for variants absent from large population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0.
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No prior evidence identifies a different nucleotide change at codon 58 resulting in the same amino acid substitution (p.Met58Val) that is classified as pathogenic. No established pathogenic variant with the same amino acid change was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No pathogenic variant encoding p.Met58Val from a different nucleotide change was identified.
Still missing
- Exhaustive search for same-amino-acid pathogenic variants at codon 58 not performed.
Sources
PS2 No de novo observation has been reported for this variant. No parental testing data or de novo confirmation is available in ClinVar submissions or the reviewed literature. Details ▾Hide ▴
Evidence considered
- No de novo confirmation in any ClinVar submission or published report.
Still missing
- De novo status cannot be assessed without parental genotypes.
Sources
PS3 No well-established in vitro or in vivo functional studies have been identified for this specific variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. The variant is absent from COSMIC, and no dedicated functional study of p.Met58Val was found in the reviewed literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
- COSMIC: variant not reported in somatic cancers.
Still missing
- No dedicated functional assays for p.Met58Val available.
Sources
PS4 The prevalence of this variant in affected individuals has not been established. Six clinical laboratories have submitted this variant to ClinVar, all classifying it as Uncertain Significance, and none of the reviewed publications report this variant in affected patients. No case-control or cohort data demonstrate enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS submitted by 6 clinical labs
- no case counts or phenotype details.
- gnomAD: variant is absent
- precluding odds-ratio calculation.
Still missing
- No published case reports or cohort studies reporting NM_003000.3:c.172A>G in affected individuals.
Sources
PM1 The variant does not lie within a statistically significant mutational hotspot per Cancer Hotspots analysis, and no evidence establishes residue 58 as a critical or well-established functional domain in SDHB with supporting functional or structural data specific to this position. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue 58 is not a statistically significant hotspot.
Still missing
- Structural/functional domain analysis for SDHB residue 58 not available
- a human reviewer may consider whether the N-terminal region constitutes a critical domain.
PM6 No de novo observation has been reported for this variant. No parental genotype data or de novo confirmation is available in ClinVar submissions or the reviewed literature. Details ▾Hide ▴
Evidence considered
- No de novo confirmation in any available source.
Still missing
- Parental genotypes unavailable.
Sources
PP1 No cosegregation data have been reported for this variant. No family studies or segregation analyses involving NM_003000.3:c.172A>G were identified in ClinVar submissions or the reviewed literature. Details ▾Hide ▴
Evidence considered
- No segregation data in any available source.
Still missing
- No family studies available.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.00). BayesDel score is 0.338, which falls in the indeterminate range and does not reach a pathogenic threshold. REVEL and HCI prior scores are unavailable. The available in silico evidence is insufficient to meet PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score 0.00
- no predicted splice impact.
- BayesDel: 0.338 (indeterminate range).
- REVEL: not available.
- HCI prior: not available for SDHB.
Still missing
- REVEL score unavailable for this variant.
Sources
spliceai ↗bayesdel
PP4 No patient-specific phenotype data are available for this variant. ClinVar submissions do not include clinical phenotypes, and no published case reports describe the phenotype of individuals harboring NM_003000.3:c.172A>G. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotype data associated with this variant in ClinVar or published literature.
Still missing
- No patient phenotype information available.
Sources
PP5 No reputable source has recently reported this variant as pathogenic. ClinVar classification is Uncertain Significance from six clinical laboratories, and no published report asserts pathogenicity for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- not reported as pathogenic.
Sources
BA1 The variant is absent from gnomAD v2.1 and v4.1. An allele frequency >1% is not observed in any population database. BA1 is not met. Details ▾Hide ▴
BS1 The variant is absent from gnomAD v2.1 and v4.1. An allele frequency >0.3% is not observed in any population database. BS1 is not met. Details ▾Hide ▴
BS2 No data are available regarding observation of this variant in trans with a pathogenic SDHB variant in a healthy individual. SDHB-associated disease follows autosomal dominant inheritance, and BS2 is typically not applicable. No such observation has been reported. Details ▾Hide ▴
Evidence considered
- No trans-configuration data available.
BS3 No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this specific variant. No dedicated functional assay of p.Met58Val was identified in the reviewed literature, OncoKB, or other evidence sources. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific benign functional evidence.
- No functional studies of p.Met58Val identified in the literature.
Still missing
- No functional characterization of p.Met58Val available.
Sources
BS4 No segregation data are available for this variant. No family studies demonstrating lack of cosegregation with disease have been reported for NM_003000.3:c.172A>G. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies available.
BP2 No observation of this variant in trans with a pathogenic SDHB variant in a healthy individual has been reported. SDHB-associated disease is autosomal dominant, and no trans data are available. Details ▾Hide ▴
Evidence considered
- No trans-configuration data available.
BP4 Multiple lines of computational evidence do not support a benign effect. SpliceAI predicts no splice impact (max delta 0.00). BayesDel score is 0.338, which is in the indeterminate range and does not reach a benign threshold. REVEL is unavailable. The available evidence is insufficient to meet BP4, which requires multiple lines of computational evidence suggesting no impact on gene or gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.00.
- BayesDel: 0.338 (indeterminate).
- REVEL: unavailable.
Still missing
- REVEL score unavailable.
Sources
spliceai ↗bayesdel
BP5 No evidence demonstrates that this variant was found in a case with an alternate molecular basis for disease. No data are available to support BP5. Details ▾Hide ▴
Evidence considered
- No data on alternate molecular cause available.
Still missing
- No clinical context available to assess alternate molecular basis.
BP6 No reputable source has reported this variant as benign. ClinVar classification is Uncertain Significance from six clinical laboratories. BP6 is not met. Details ▾Hide ▴
PS5 No reputable source has recently reported this variant as pathogenic. ClinVar classification is Uncertain Significance from six clinical laboratories, and no published report asserts pathogenicity for this variant. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PP2 PP2 requires quantitative evidence that the gene has a low rate of benign missense variation (e.g., high missense Z-score or low missense constraint metric). SDHB is recognized as a tumor suppressor gene in which missense variants are a known disease mechanism; however, no gene-level missense constraint data (such as gnomAD missense Z-score or HCI prior probability) were available in the evidence records to support formal application of this criterion. Details ▾Hide ▴
Evidence considered
- SDHB is a known tumor suppressor with pathogenic missense variants
- but no formal constraint metrics were available to apply PP2.
Still missing
- gnomAD missense Z-score not retrieved.
- HCI prior probability not available for SDHB.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_003000.3:c.172A>G is a missense substitution (p.Met58Val) in SDHB exon 2 and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Met58Val)
- not a null variant
- generic PVS1 framework does not apply.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. SDHB-associated hereditary pheochromocytoma-paraganglioma is autosomal dominant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. NM_003000.3:c.172A>G is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic missense variant at the same amino acid residue (Met58) was identified as a comparator. The automated PM5 candidate harvesting found no same-residue candidates, and manual review of ClinVar did not reveal a different missense change at codon 58 classified as pathogenic. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic missense comparator identified in PM5 candidate search.
Sources
pm5_candidatesclinvar ↗
BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. SDHB is well-established to have pathogenic missense variants in hereditary pheochromocytoma-paraganglioma, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- SDHB has known pathogenic missense variants
- missense is a recognized disease mechanism.
Sources
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_003000.3:c.172A>G is a missense variant (p.Met58Val), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- SDHB
- Transcript
- NM_003000.3
- Coding (HGVS c.)
- NM_003000.3:c.172A>G
- Protein (HGVS p.)
- NP_002991.2:p.(Met58Val)
- GRCh38
- chr1:17044789 T>C
- GRCh37
- chr1:17371284 T>C
- ClinVar
- 459138
Gene diagram
Every interpreted variant in SDHB, mapped onto the exon structure of NM_003000.3. Select a row to find it on the plot.
SDHBNM_003000.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SDHB
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.338
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta score 0.00). BayesDel score is 0.338, which falls in the indeterminate range and does not reach a pathogenic threshold. REVEL and HCI prior scores are unavailable. The available in silico evidence is insufficient to meet PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score 0.00
- no predicted splice impact.
- BayesDel: 0.338 (indeterminate range).
- REVEL: not available.
- HCI prior: not available for SDHB.
Still missing
- REVEL score unavailable for this variant.
Sources
spliceai ↗bayesdel
BP4 Multiple lines of computational evidence do not support a benign effect. SpliceAI predicts no splice impact (max delta 0.00). BayesDel score is 0.338, which is in the indeterminate range and does not reach a benign threshold. REVEL is unavailable. The available evidence is insufficient to meet BP4, which requires multiple lines of computational evidence suggesting no impact on gene or gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.00.
- BayesDel: 0.338 (indeterminate).
- REVEL: unavailable.
Still missing
- REVEL score unavailable.
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_003000.3:c.172A>G is a missense variant (p.Met58Val), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.338173.
12 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 20816580 ↗Endocrine cancer predisposition syndromes: hereditary paraganglioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, and hereditary thyroid cancer.No paper-specific finding is recorded.
-
PMID 23852704 ↗Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.Duffy MJ et al. · 2014No paper-specific finding is recorded.
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 20065170 ↗American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.No paper-specific finding is recorded.
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PMID 20301715 ↗Hereditary Paraganglioma-Pheochromocytoma Syndromes.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 20664475 ↗The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.Chen H et al. · 2010No paper-specific finding is recorded.
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.No paper-specific finding is recorded.
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PMID 24319509 ↗Canadian guideline on genetic screening for hereditary renal cell cancers.Reaume MN et al. · 2013No paper-specific finding is recorded.
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PMID 22685257 ↗The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation.Wong NA et al. · 2012No paper-specific finding is recorded.
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PMID 24893135 ↗Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.Lenders JW et al. · 2014No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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PMID 33939658 ↗The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
5 Uncertain significance · 1 Uncertain Significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/101200173
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/459138/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-17371284-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-17044789-T-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003000.3%3Ac.172A…
- OncoKB ↗www.oncokb.org/gene/SDHB/M58V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SDHB+c.172A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 459138)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.338173.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SDHB, a subunit of succinate dehydrogenase, is infrequently altered in cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.