NM_003000.3:c.172A>G

SDHB · NP_002991.2:p.(Met58Val) · NM_003000.3

GRCh37: chr1:17371284 T>C · GRCh38: chr1:17044789 T>C

Gene: SDHB Transcript: NM_003000.3

Final call

VUS

PM2 supporting

Variant details

Gene

SDHB

Transcript

NM_003000.3

Protein

NP_002991.2:p.(Met58Val)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 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).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not met	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.	clinvar
PS3	Not met	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.	oncokb
PS4	Not met	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.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	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.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	No 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.	pm5_candidates clinvar
PM6	Not met	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.	clinvar
PP1	Not met	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.	clinvar
PP2	Not assessed	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.
PP3	Not met	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.	spliceai bayesdel
PP4	Not met	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.	clinvar
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.
BS3	Not met	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.	oncokb
BS4	Not met	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.
BP1	N/A	BP1 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.	cspec
BP2	Not met	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.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single-nucleotide substitution, not an in-frame indel.
BP4	Not met	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.	spliceai bayesdel
BP5	Not met	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.
BP6	Not met	No reputable source has reported this variant as benign. ClinVar classification is Uncertain Significance from six clinical laboratories. BP6 is not met.	clinvar
BP7	N/A	BP7 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.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. SDHB-associated hereditary pheochromocytoma-paraganglioma is autosomal dominant.
PM4	N/A	PM4 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.

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