Variant classification summary

NM_000454.5:c.14C>T

SOD1 · NP_000445.1:p.(Ala5Val) · NM_000454.5

GRCh37: chr21:33032096 C>T · GRCh38: chr21:31659783 C>T

Gene: SOD1 Transcript: NM_000454.5

Final call

Likely Pathogenic

PS1 strong PS3 moderate PM2 supporting PP3 moderate

Variant details

Gene

SOD1

Transcript

NM_000454.5

Protein

NP_000445.1:p.(Ala5Val)

gnomAD AF

1.2392080469213735e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS1 strong because the same Ala-to-Val SOD1 substitution is reported as pathogenic A4V in ALS.

2

Pathogenic evidence: PS3 moderate because independent assays demonstrated SOD1 destabilization, abnormal dimer behavior, and aggregation-related abnormalities.

3

Pathogenic evidence: PM2 supporting because gnomAD v4.1 group maximum FAF is 2.8e-07 with zero homozygotes.

4

Pathogenic evidence: PP3 moderate because REVEL 0.853 exceeds the generic deleterious threshold of 0.773.

Final determination: Generic ACMG/AMP 2015 fallback rules classify the variant as Likely Pathogenic when 1 strong and 1–2 moderate pathogenic criteria are satisfied; PS1 strong plus PS3 and PP3 moderate meets this rule.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met: The same Ala-to-Val substitution is reported as pathogenic SOD1 A4V in multiple ALS studies, despite the one-residue mature-protein numbering offset.	PMID:19176896 PMID:19800308 PMID:21549128
PS2	Not assessed	Not assessed: no documented proband with both maternity and paternity confirmed, parental variant testing, and no family history.	PMID:19176896 PMID:19483195
PS3	Met	Met at moderate strength: independent A4V assays showed at least 18-fold faster dimer dissociation than wild-type SOD1 and reproducible structural, stability, and aggregation abnormalities.	PMID:21549128 PMID:19800308 PMID:19483195
PS4	Not assessed	Not assessed: PMID:19176896 reports a linked haplotype association (case frequency 0.23 versus control 0.0), but no variant-specific OR/RR or 95% CI for c.14C>T.	PMID:19176896
PM1	Not met	Not met: Residue 5 has no approved critical-domain or hotspot evidence, and the cancer-hotspot search returned no statistically significant hotspot.	cspec hotspots PMID:12482932
PM2	Met	Met at supporting: gnomAD v4.1 grpmax FAF is 2.8e-07, below the <=0.0001 PM2 threshold, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: SOD1 A4V/A5V is documented in autosomal-dominant ALS, whereas PM3 requires a recessive disorder and a pathogenic variant in trans.	PMID:19176896
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: No reliable different pathogenic missense substitution at SOD1 residue 5 is documented in the supplied evidence.	pm5_candidates
PM6	Not assessed	Not assessed: no specific affected patient is documented with an assumed de novo variant and missing parental confirmation.	PMID:19176896 PMID:19483195
PP1	Not assessed	Not assessed: 54 A4V families are reported, but no variant-specific affected-relative genotypes or informative meioses are provided.	PMID:19176896 PMID:19483195
PP2	Not assessed	Not assessed: SOD1 has many disease-associated missense mutations, but no supplied gene-wide benign-missense rate establishes the PP2 threshold.	PMID:12482932 PMID:19483195 PMID:20184893
PP3	Met	Met at moderate strength: missense REVEL 0.853 meets the >=0.773 PP3 threshold.	revel
PP4	Not met	Not met: ALS, even with rapid lower-motor-neuron progression, is not highly specific for a single genetic etiology such as SOD1.	PMID:19176896
PP5	Not met	Not met: no exact-variant ClinVar expert-panel pathogenic classification exists, and the published evidence is available for independent evaluation.	clinvar PMID:19176896
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.8e-07, far below the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.8e-07, well below the generic >=0.01 BS1 frequency threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD has zero homozygotes, but carrier ages, health status, and penetrance are not documented.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not met	Not met: all variant-specific functional results identified abnormal SOD1 stability, folding, dimerization, or aggregation rather than no damaging effect on protein function or splicing.	PMID:21549128 PMID:19800308 PMID:19483195
BS4	Not assessed	Not assessed: no affected relative is documented as genotype-negative, and no family-level non-segregation analysis is available.	PMID:19176896 PMID:19483195
BP1	Not met	Not met: SOD1 disease is characterized by numerous point or missense mutations and gain of function, not primarily truncating variants.	PMID:12482932 PMID:20184893
BP2	Not assessed	Not assessed: no second pathogenic variant or validated cis/trans phase is documented for the SOD1 A4V/A5V case.	PMID:19176896
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL 0.853 exceeds the <=0.29 BP4 supporting threshold.	revel
BP5	Not assessed	Not assessed: no documented alternate molecular basis for the disease is available for this case.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign classification or unavailable reputable-source benign report is present.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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