NM_003002.4:c.110A>T

SDHD · NP_002993.1:p.(Asp37Val) · NM_003002.4

GRCh37: chr11:111958638 A>T · GRCh38: chr11:112087914 A>T

Gene: SDHD Transcript: NM_003002.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

SDHD

Transcript

NM_003002.4

Protein

NP_002993.1:p.(Asp37Val)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_003002.4:c.110A>T (p.Asp37Val) in SDHD is absent from all gnomAD population databases (v2.1, v4.1, gnomAD-Canada), supporting PM2 at supporting strength.

In silico predictions support a deleterious effect: REVEL score 0.701 and SpliceAI max delta 0.30 suggest possible functional and splice impact, meeting PP3 at supporting strength.

No variant-specific functional studies, case reports, segregation data, or expert panel classifications are available. ClinVar contains two single-submitter classifications (Uncertain significance, Likely pathogenic), neither from an expert panel.

With only PM2 (supporting) and PP3 (supporting) met, the evidence is insufficient to classify this variant as pathogenic or likely pathogenic under the generic ACMG/AMP 2015 framework. The variant is classified as a Variant of Uncertain Significance (VUS).

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_003002.4:c.110A>T (p.Asp37Val) does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No evidence that the same amino acid change (p.Asp37Val) arising from a different nucleotide substitution has been previously established as pathogenic. No ClinVar entries or literature reports identify a different nucleotide change producing the same Asp37Val substitution.	clinvar
PS2	Not assessed	No de novo testing data available. No report of this variant confirmed as de novo in any publication or clinical database.
PS3	Not met	No variant-specific functional studies were identified for NM_003002.4:c.110A>T (p.Asp37Val). OncoKB records this variant as having unknown oncogenic effect. No publications with experimental functional characterization of this exact variant or a systematically characterized range encompassing position 37 were found.	oncokb
PS4	Not met	No case reports or patient observations documenting this specific variant were identified in the literature. The ClinVar-associated PMIDs are clinical practice guidelines and review articles that do not mention NM_003002.4:c.110A>T.	clinvar
PS5	N/A	PS5 is not a criterion defined in the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868). The standard ACMG criteria do not include PS5.	generic_acmg_combination_rules
PM1	Not met	Position 37 of SDHD is not within a statistically significant mutational hotspot per cancerhotspots.org, and no literature evidence in the case materials establishes this N-terminal region as a well-characterized critical functional domain with demonstrated variant-level impact at this residue.	oncokb
PM2	Met	NM_003002.4:c.110A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with allele frequency well below the 0.1% threshold for PM2 under the generic ACMG framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense comparators at the same residue (position 37) with a different amino acid change were identified. The automated PM5 candidate search returned zero candidates.	pm5_candidates
PM6	Not assessed	No de novo confirmation data available for this variant. No publication or clinical report documents NM_003002.4:c.110A>T as a confirmed de novo event.
PP1	Not assessed	No segregation data available. No family studies or co-segregation analysis has been performed for this variant.
PP2	Not met	No gene-specific missense constraint metric is available for SDHD. The HCI prior was not found for this gene, and no custom PP2 score exists. Without statistical evidence that SDHD has a low rate of benign missense variation, PP2 cannot be applied.
PP3	Met	Multiple in silico tools support a deleterious effect. REVEL score of 0.701 exceeds the typical 0.5 threshold for pathogenicity prediction. SpliceAI predicts a possible splice alteration with a maximum delta score of 0.30 (DS_AL=0.30, DS_DL=0.27). BayesDel score of 0.257 is not independently supportive but does not contradict.	revel spliceai bayesdel
PP4	Not assessed	Patient phenotype information was not provided in the case materials. Phenotype specificity for hereditary paraganglioma-pheochromocytoma syndrome cannot be evaluated without clinical data.
PP5	Not met	ClinVar review status for variation 940748 is 'criteria provided, single submitter' — not a 3-star expert panel classification. Under the PP5 rule requiring a 3-star expert panel assertion of pathogenicity, this does not qualify. The two submissions are VUS (Invitae) and Likely Pathogenic (Ambry Genetics), neither from an expert panel.	clinvar
BA1	Not met	The variant is absent from all gnomAD population databases. Allele frequency does not exceed the 1% threshold required for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all gnomAD population databases. Allele frequency does not exceed the 0.3% threshold required for BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation of this variant in healthy adult controls is available. The variant is absent from population databases, so the question of observation in healthy individuals is moot.
BS3	Not assessed	No functional studies demonstrating no damaging effect on protein function or splicing are available for this variant.
BS4	Not assessed	No segregation data available to evaluate lack of co-segregation with disease.
BP1	Not met	Although SDHD is a tumor suppressor gene where loss-of-function is the primary disease mechanism, pathogenic missense variants in SDHD are well-established in hereditary paraganglioma-pheochromocytoma syndromes. BP1 is intended for genes where only truncating variants cause disease, which does not apply to SDHD.
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic variant in SDHD.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; NM_003002.4:c.110A>T is a missense substitution.
BP4	Not met	Multiple in silico tools predict a deleterious rather than benign effect. REVEL score of 0.701 supports pathogenicity and SpliceAI max delta of 0.30 suggests possible splice alteration. These predictions do not support a benign interpretation.	revel spliceai bayesdel
BP5	Not assessed	No evidence of an alternate molecular basis for disease in a case where this variant was observed.
BP6	Not met	No expert panel has classified this variant as benign or likely benign. ClinVar review status is 'criteria provided, single submitter' with submissions of VUS and Likely Pathogenic — neither constitutes a 3-star expert panel benign assertion.	clinvar
BP7	N/A	BP7 applies to synonymous variants without predicted splice effect. NM_003002.4:c.110A>T is a missense variant (p.Asp37Val), not a synonymous substitution.
PM3	N/A	PM3 requires observation in trans with a pathogenic variant for recessive disorders; SDHD-associated disease follows autosomal dominant inheritance with paternal parent-of-origin effects, making PM3 inapplicable.
PM4	N/A	PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss); NM_003002.4:c.110A>T is a missense substitution with no protein length change.

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