Classification rationale

PM2 BP7 VUS

SDHA c.840C>T

The SDHA c.840C>T (p.Ile280=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Likely benign with criteria provided from a single submitter.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the default PM2 rarity threshold of 0.1% and does not reach the BS1 (>0.3%) or BA1 (>1%) benign frequency thresholds.² In silico assessment is consistent with a benign synonymous effect, as the variant does not change the amino acid sequence and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.³

PM2 + BP7 → VUS

1 clinvar ↗

2 gnomad_v4 ↗

3 spliceai ↗

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.

Gene diagram · NM_004168.4 · variants mapped to exon structure

SDHA NM_004168.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 review Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the default PM2 rarity threshold of 0.1% for generic ACMG population assessment.

gnomAD v2.1: absentgnomAD v4.1: absent

gnomad_v2 ↗gnomad_v4 ↗

BP7 review Benign

This is a synonymous variant, p.(Ile280=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting no expected effect on RNA splicing or protein sequence.

Protein consequence is NP_004159.2:p.(Ile280=)SpliceAI max delta score = 0.04

spliceai ↗

Assessed · not applied · 5 not met · 13 not assessed

Pathogenic

PS2 No de novo data with confirmed maternity and paternity were identified for this variant.

PS3 No well-established functional studies demonstrating a damaging effect of this variant on SDHA function were identified.

PS4 Available evidence does not show that this variant is enriched in affected individuals compared with controls.

PM1 This variant has not been identified in a mutational hotspot or other well-established critical functional domain without benign variation.

PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context.

PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant.

PP1 No segregation data were identified to show that this variant tracks with disease in affected family members.

PP3 Available computational evidence does not support a deleterious effect.

PP4 No phenotype or family history data were identified to show a clinical presentation highly specific for an SDHA-related disorder attributable to this variant.

PP5 ClinVar lists this variant as Likely benign with criteria provided from a single submitter rather than as a pathogenic assertion from an expert panel or other established authoritative source, so PP5 is not applied.

Benign

BA1 This variant does not meet BA1 because it is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the 1% benign stand-alone frequency threshold.

BS1 This variant does not meet BS1 because it is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the default 0.3% benign strong frequency threshold.

BS2 No data were identified showing this variant in healthy adult individuals in a context sufficient to support BS2.

BS3 No well-established functional studies demonstrating no damaging effect of this variant were identified.

BS4 No family data were identified showing lack of segregation of this variant with disease.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2.

BP5 No alternate molecular explanation for the phenotype was identified that would support BP5.

BP6 ClinVar lists this variant as Likely benign, but the available assertion is from a single submitter rather than an expert panel or other established authoritative benign source, so BP6 is not applied.

N/A · 8 PVS1 · PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

Hotspots ↗

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots

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