NM_000021.3(PSEN1):c.1234G>A

PSEN1 · NP_000012.1:p.(Val412Ile) · NM_000021.3

GRCh37: chr14:73683938 G>A · GRCh38: chr14:73217230 G>A

Gene: PSEN1 Transcript: NM_000021.3

Final call

VUS

PM2 supporting PP1 supporting

Variant details

Gene

PSEN1

Transcript

NM_000021.3

Protein

NP_000012.1:p.(Val412Ile)

gnomAD AF

1.4254690412914998e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000021.3(PSEN1):c.1234G>A (p.Val412Ile) is extremely rare in population databases, with an allele frequency of 0.00107% in gnomAD v2.1 (3/280,740 alleles) and 0.00143% in gnomAD v4.1 (23/1,613,504 alleles), meeting PM2 at supporting level.

The variant co-segregates with early-onset frontotemporal dementia in 4 affected individuals across 2 generations in the FUS family (Bernardi et al. 2009, PMID:18314228), meeting PP1 at supporting level. However, incomplete penetrance is noted with 2 cognitively healthy carriers identified at ages 49 and 71 in follow-up (Bernardi et al. 2011, PMID:21297264).

No variant-specific functional data are available. The in vitro study of 138 PSEN1 pathogenic mutations by Sun et al. (PMID:27930341) did not include p.Val412Ile, as it is currently classified as a variant of uncertain significance.

In silico predictors are mixed: REVEL score is 0.679, BayesDel is 0.305, and SpliceAI predicts no splicing impact (delta=0.00). The ClinVar submitter LabCorp notes 3 of 5 in silico tools predict a benign effect, precluding application of PP3.

This variant is classified as Uncertain significance by 3 clinical laboratories in ClinVar (ID: 1318725). No submitter classifies it as pathogenic or likely pathogenic.

Overall, the evidence for pathogenicity is limited to one supporting criterion (PM2) and one supporting criterion (PP1). With only 2 supporting criteria met and no moderate or strong pathogenic criteria, the variant does not reach the threshold for Likely Pathogenic (which requires 2 supporting + 1 moderate, or variants thereof). The classification remains Uncertain significance.

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	Not met	NM_000021.3:c.1234G>A is a missense variant (p.Val412Ile), not a null variant (nonsense, frameshift, or canonical splice). Generic PVS1 framework requires null-variant types; this substitution does not qualify.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No pathogenic variant at the same nucleotide position (c.1234) has been identified. PS1 requires a different nucleotide change at the same position that is known to be pathogenic.	clinvar pm5_candidates
PS2	Not met	No confirmed de novo occurrence with maternity and paternity confirmation has been reported for this variant.
PS3	Not met	No variant-specific functional data are available. The in vitro γ-secretase assay by Sun et al. (PMID:27930341) analyzed 138 pathogenic PSEN1 mutations; p.Val412Ile, currently classified as VUS, was not among the variants studied.	PMID:27930341
PS4	Not met	The variant has been observed in a single family (FUS family) with 4 affected individuals across 2 generations. No case-control study or statistically significant enrichment in affected vs. control populations is available.	PMID:18314228 PMID:21297264
PS5	Not met	No evidence from genome-wide association or linkage studies establishes this specific variant as disease-causing.
PM1	Not met	Residue 412 does not lie in a statistically significant mutational hotspot (hotspots residue_significant: false). No domain-level evidence establishes codon 412 as a critical functional domain without benign variation.
PM2	Met	This variant is extremely rare in population databases, well below the 0.1% PM2 threshold. gnomAD v2.1: 3/280,740 alleles (AF=0.00107%); gnomAD v4.1: 23/1,613,504 alleles (AF=0.00143%); grpmax FAF=2.55e-05. Absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Val412) has been identified. Automated PM5 candidate search found zero same-residue pathogenic comparators.	pm5_candidates
PM6	Not met	No de novo observation (with or without confirmed parentage) has been reported for this variant in any reviewed source.
PP1	Met	The variant co-segregates with early-onset frontotemporal dementia in 4 affected individuals over 2 generations in the FUS family (PMID:18314228). However, incomplete penetrance is noted: 2 cognitively healthy elderly carriers were identified (IV-5 at age 49, III-2 at age 71; PMID:21297264), which tempers the segregation signal.	PMID:18314228 PMID:21297264
PP2	Not assessed	Insufficient gene-level constraint metrics for PSEN1 available in this case. PP2 requires a gene with low rate of benign missense variation and high rate of pathogenic missense variants, but gnomAD missense constraint scores (Z-score) were not provided.
PP3	Not met	In silico predictors yield mixed results, not meeting the threshold for multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.679 (borderline), BayesDel is 0.305 (marginally above the 0.27 damaging threshold), but ClinVar submitter LabCorp notes 3 of 5 in silico tools predict a benign effect. SpliceAI predicts no splicing impact (max delta=0.00).	revel bayesdel spliceai
PP4	Not met	The proband's phenotype (early-onset frontotemporal dementia) is not highly specific for PSEN1-related disease. FTD has significant genetic heterogeneity (MAPT, PGRN, C9orf72, etc.) and overlapping clinical features with other neurodegenerative conditions.	PMID:18314228
PP5	Not met	No reputable source (e.g., clinical laboratory with appropriate quality measures, expert panel, or clinical database) has classified this variant as pathogenic. Current ClinVar classification is Uncertain significance.	clinvar
BA1	Not met	Allele frequency is far below the 1% BA1 threshold. gnomAD v2.1 AF=0.00107%, gnomAD v4.1 AF=0.00143%.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is far below the 0.3% BS1 threshold. gnomAD v2.1 AF=0.00107%, gnomAD v4.1 AF=0.00143%.	gnomad_v2 gnomad_v4
BS2	Not met	Two cognitively healthy elderly carriers of PSEN1 p.Val412Ile were observed in the FUS family (ages 49 and 71; PMID:21297264). However, PSEN1-associated disease exhibits age-dependent penetrance with reported onset as late as 78 years. Observation of healthy carriers at these ages, while notable, is insufficient to rule out pathogenic potential given the known variable penetrance and age-dependent expressivity of PSEN1 variants.	PMID:21297264
BS3	Not met	No well-established functional studies demonstrate a benign effect for this specific variant.
BS4	Not met	The variant segregates with disease in the FUS family (4 affected carriers). Lack of segregation is not observed; two healthy carriers reflect incomplete penetrance, not non-segregation.	PMID:18314228 PMID:21297264
BP1	N/A	PSEN1-associated disease is primarily driven by missense variants, not truncating variants. BP1 applies only to genes where truncating variants are the predominant disease mechanism.
BP2	Not met	Not observed in trans with a known pathogenic PSEN1 variant. No data available to assess this criterion.
BP3	N/A	Variant is a single-nucleotide substitution, not an in-frame indel; BP3 applies exclusively to in-frame deletions/insertions in repetitive regions.
BP4	Not met	Computational evidence is mixed and does not provide multiple lines of support for a benign effect. REVEL 0.679 and BayesDel 0.305 both lean toward damaging, not benign. SpliceAI predicts no splicing impact but this alone is insufficient for BP4.	revel bayesdel spliceai
BP5	Not met	No case has been identified where this variant is found in an individual with an alternate definitive molecular cause explaining the phenotype. The PRNP co-mutation in the FUS family does not constitute an alternate cause, as PSEN1-only carriers were also affected.	PMID:21297264
BP6	Not met	No reputable source classifies this variant as benign. ClinVar consensus is Uncertain significance (3 laboratories, criteria provided, single submitter).	clinvar
BP7	N/A	NM_000021.3:c.1234G>A is a missense variant (p.Val412Ile), not a synonymous or intronic variant. BP7 applies only to synonymous variants without predicted splicing impact.
PM3	N/A	PSEN1-associated disease is autosomal dominant; PM3 (observation in trans with a pathogenic variant) is not applicable to dominant disorders with established dominant mechanism.
PM4	N/A	Variant is a single-nucleotide missense substitution, not a protein-length-altering change (in-frame deletion/insertion, stop-loss, or initiation codon).

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