LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-05
Case ID: NM_170707.4_c.568C_T_20261105_051742
Framework: ACMG/AMP 2015
Variant classification summary

NM_170707.4:c.568C>T

LMNA  · NP_733821.1:p.(Arg190Trp)  · NM_170707.4
GRCh37: chr1:156104248 C>T  ·  GRCh38: chr1:156134457 C>T
Gene: LMNA Transcript: NM_170707.4
Final call
Pathogenic
PS1 strong PM1 moderate PM2 supporting PP1 supporting PP3 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
LMNA
Transcript
NM_170707.4
Protein
NP_733821.1:p.(Arg190Trp)
gnomAD AF
6.195640994821683e-07 (v4.1)
ClinVar
Pathogenic
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 strong is supported by independent reports of the exact p.Arg190Trp substitution in affected cohorts.
2
Pathogenic: PM1 moderate is supported by the variant's location in the conserved coil 1b central rod domain.
3
Pathogenic: PM2 supporting is supported by gnomAD v4.1 frequency of 6.20e-07 and zero homozygotes.
4
Pathogenic: PP1 supporting is supported by co-segregation with disease in two affected family members.
5
Pathogenic: PP3 moderate is supported by a REVEL score of 0.848.
Final determination: Under the generic ACMG/AMP 2015 fallback, 1 strong pathogenic criterion plus 2 moderate and 2 supporting pathogenic criteria yields Pathogenic; no benign rule is satisfied.
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 exact LMNA p.Arg190Trp substitution was independently reported in affected cohorts and listed among pathogenic or likely pathogenic variants.
PMID:22199124 PMID:11897440 PMID:32041989
PS2 Not assessed Not assessed: no documented parental genotypes or confirmed maternity and paternity establish this variant as de novo in a patient without family history.
PMID:11897440 PMID:22199124 PMID:32041989
PS3 Not assessed Not assessed: available reports provide clinical observations and in-silico predictions but no validated functional assay result for LMNA p.Arg190Trp.
PMID:11897440 PMID:16537768 PMID:22199124 PMID:28416588 PMID:32041989
PS4 Not met Not met: variant-specific cases and control absence were reported, but no OR or RR >5.0 with a 95% confidence interval excluding 1.0 was established.
PMID:11897440 PMID:22199124 PMID:32041989
PM1 Met Met, Arg190 is in LMNA's conserved coil 1b rod domain, with no p.Arg190Trp observed among 300 unrelated controls.
PMID:11897440 PMID:22199124
PM2 Met Met at supporting strength: gnomAD v4.1 shows 1/1,614,038 alleles, AF 6.20e-07, zero homozygotes, below the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no report establishes this variant in trans with a pathogenic allele or provides parental/offspring phase testing for a recessive LMNA disorder.
PMID:11897440 PMID:22199124 PMID:32041989
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 verified different pathogenic missense substitution at LMNA residue Arg190 was identified.
pm5_candidates
PM6 Not assessed Not assessed: no documented assumed de novo event or proband-specific parental testing supports PM6.
PMID:11897440 PMID:22199124 PMID:32041989
PP1 Met Met at supporting strength: p.Arg190Trp is reported in family D with two affected carriers, D-I-2 and D-II-1, while younger carriers lacked baseline signs.
PMID:11897440
PP2 Not assessed Not assessed, the available cohort count of six missense and one truncating LMNA carrier does not establish PP2's two gene-level requirements.
PMID:28416588
PP3 Met Met at moderate strength: missense REVEL score 0.848 exceeds the PP3 moderate threshold of 0.773 but is below the strong threshold of 0.932.
revel
PP4 Not met Not met: dilated cardiomyopathy, conduction disease, and arrhythmia are compatible with LMNA disease but are not highly specific for one genetic etiology.
PMID:11897440 PMID:22199124 PMID:32041989
PP5 Not met Not met: ClinVar lists Pathogenic submissions, but no exact-variant expert-panel classification is present to support PP5.
clinvar
BA1 Not assessed Not assessed: total AF is 6.20e-07, grpmax FAF is unavailable, and the Amish estimate is only 1/912 alleles, far below the 5% BA1 threshold.
gnomad_v4 clinvar
BS1 Not assessed Not assessed: total AF is 6.20e-07, but grpmax FAF and disease-specific maximum-credible-frequency inputs are unavailable for the 1% BS1 decision.
gnomad_v4
BS2 Not met Not met: the 25-year-old carrier had non-sustained ventricular tachycardia, and the family shows adult-onset variable expression rather than full early-age penetrance.
PMID:22199124 PMID:11897440
BS3 Not assessed Not assessed: no variant-specific functional or splicing study demonstrates that LMNA p.Arg190Trp has no damaging effect.
PMID:11897440 PMID:16537768 PMID:22199124 PMID:28416588 PMID:32041989
BS4 Not assessed Not assessed: no affected non-carriers are documented; the reported non-affected individuals were variant carriers, not evidence of absent segregation.
PMID:11897440 PMID:22199124
BP1 Not assessed Not assessed, one cohort reported one truncating versus six missense LMNA carriers but cannot establish a primarily truncating disease mechanism.
PMID:28416588
BP2 Not assessed Not assessed: no phase-resolved observation places this variant in trans or cis with a pathogenic variant as required for BP2.
PMID:11897440 PMID:22199124 PMID:32041989
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 score 0.848 is above the BP4 supporting threshold of 0.29, so it does not support a benign computational effect.
revel
BP5 Not met Not met: no reviewed case documents this variant together with a confirmed alternate molecular basis for the disease.
PMID:11897440 PMID:22199124 PMID:32041989
BP6 Not met Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; the available aggregate label is Pathogenic.
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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