LMNA c.568C>T, p.Arg190Trp

Reasoning

The variant is LMNA p.Arg190Trp (c.568C>T). Independent full-text reports explicitly identify the same amino-acid substitution, Arg190Trp/R190W, in affected DCM or ARVC families and cohorts, including a report describing it as pathogenic or likely pathogenic. This is the same amino-acid change, not merely a different change at the same residue, and the cited reports describe a missense protein-level observation rather than a splice-only effect.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy, Results/Family A: explicitly reports c.568C>T (p.Arg190Trp) and the same mutation in a son.
• Autosomal dominant dilated cardiomyopathy with atrioventricular block, Results/Genetic studies and Table 1: explicitly reports Arg190Trp in LMNA exon 3.
• Genetic Basis and Genotype-Phenotype Correlations in Han Chinese Patients with Idiopathic Dilated Cardiomyopathy, Results/Table 3: explicitly reports c.568C>T, p.R190W, among pathogenic or likely pathogenic missense variants and in two unrelated DCM patients.

Sources

Reasoning

Arg190 lies in the LMNA coil 1b central rod domain. A full-text LMNA study places Arg190Trp specifically in the coil 1b rod domain and describes the affected amino-acid positions as highly conserved; another reports the variant in the conserved central rod domain and found no occurrence among 300 unrelated UK Caucasian controls. These observations support a critical, well-established disease-relevant domain without documented benign variation in the cited control sample. No VCEP domain table or gene-specific hotspot specification exists for LMNA, so this is judged under the generic PM1 definition and retained for expert confirmation of whether the rod domain satisfies the generic critical-domain standard.

Rule

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

Evidence considered

• Autosomal dominant dilated cardiomyopathy with atrioventricular block, Results/Genetic studies and Table 1: states Arg190Trp is in exon 3, coil 1b, rod domain, and reports absence from 107 normal subjects.
• Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy, Results/Pathogenicity of individual mutations: describes Arg190Trp as affecting a conserved amino-acid position in the central rod domain and reports it was not detected among 300 unrelated UK Caucasian controls.

Still missing

• Expert confirmation that the LMNA coil 1b rod domain meets the generic ACMG/AMP critical-domain standard.

Sources

Reasoning

PM2 is met at supporting strength. The variant is absent from gnomAD v2.1 and occurs once among 1,614,038 total gnomAD v4.1 alleles, with total AF 6.195640994821683e-07 and zero homozygotes. This is below the supplied generic PM2 supporting threshold of <=0.0001. The single Amish observation remains extremely rare and has zero homozygotes; no governing VCEP requires a non-cancer or exome-only subset for this generic interpretation.

Rule

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v2.1: variant absent.
• gnomAD v4.1: total AC 1, total AN 1,614,038, total AF 6.195640994821683e-07, total homozygotes 0; genome AC 1/152,196 and exome AC 0/0.
• Generic PM2 supporting threshold: <=0.0001, ClinGen SVI recommendation to downgrade PM2 to Supporting (PMID:25741868).

Sources

Reasoning

PMID:11897440 reports LMNA p.Arg190Trp in family D, a family with autosomal-dominant dilated cardiomyopathy and atrioventricular block. The reported family includes D-I-2 with dilated cardiomyopathy at age 47 and D-II-1 with disease at age 41 and conduction abnormalities, while younger carriers had no cardiac signs at baseline. This provides co-segregation with disease in multiple affected family members, supporting PP1 at supporting strength; the unaffected younger carriers also indicate that age-dependent penetrance limits stronger interpretation.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• PMID:11897440, Results/Family D and Table 1/Figure 2: p.Arg190Trp was identified in family D with familial autosomal-dominant dilated cardiomyopathy and atrioventricular block; D-I-2 had dilated cardiomyopathy at age 47 and D-II-1 developed disease at age 41 with atrioventricular and conduction abnormalities.
• PMID:11897440 also reports several younger R190W carriers without cardiac signs at baseline, so the segregation evidence supports PP1 but does not justify a stronger level from the available follow-up.

Still missing

• Complete pedigree-level genotypes and phenotypes for all family D members
• Age-adjusted follow-up of unaffected younger carriers
• Independent segregation data from additional families

Sources

Reasoning

The variant is a missense substitution, NM_170707.4:c.568C>T (p.Arg190Trp), so the governing generic rule requires the missense REVEL path only; SpliceAI, Pangolin, and BayesDel are not used for PP3/BP4 in this situation. REVEL is 0.848, meeting the supplied generic ClinGen SVI moderate PP3 threshold of >=0.773 but not the strong threshold of >=0.932. Therefore PP3 is met at moderate strength. The absent SpliceAI result is missing data and does not alter this missense REVEL assessment.

Rule

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• NM_170707.4:c.568C>T is a missense variant encoding p.Arg190Trp, so only the REVEL path applies.
• Local REVEL lookup reports 0.848 for this variant (source_registry key: revel).
• REVEL 0.848 meets the supplied PP3 moderate threshold >=0.773 and not the strong threshold >=0.932; these generic ClinGen SVI calibration thresholds are attributed in the governing prompt to Pejaver et al. 2022, PMID:36413997.
• SpliceAI returned no score; this is missing data, not evidence for or against PP3. BayesDel has no established generic ACMG-strength calibration and is not used.

Sources

Reasoning

The reviewed literature contains variant-specific affected cases and control observations, but does not establish the ACMG/AMP PS4 requirement of OR or RR >5.0 with a 95% confidence interval excluding 1. PMID:22199124 reports p.Arg190Trp in one affected proband and one clinically unaffected carrier, with 0/300 unrelated UK Caucasian controls; this is a case-control comparison, but the reported counts do not provide a qualifying confidence interval. PMID:11897440 reports the variant in one DCM/AV block family and absence from 107 normal subjects, and PMID:32041989 reports the variant in 2/118 unrelated DCM patients with gnomAD and ExAC frequency 0; neither paper reports a qualifying OR/RR and confidence interval. The evidence therefore does not meet PS4 under the stated threshold.

Rule

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.

Evidence considered

• PMID:22199124, Results/Family A and Table 1: LMNA c.568C>T (p.Arg190Trp) was present in one affected proband and one son with normal ECG/echocardiogram but brief NSVT; the variant was absent from 300 unrelated UK Caucasian controls (1 affected carrier versus 0/300 controls).
• PMID:11897440, Results/Genetic studies and Table 1/Family D: Arg190Trp was identified in one familial DCM/atrioventricular-block family and was absent from 107 normal subjects; no case-control OR/RR and 95% CI were reported.
• PMID:32041989, Results/Landscape of genetic alterations and Table 3: p.R190W was shared by 2 unrelated patients in a 118-patient idiopathic DCM cohort and had gnomAD and ExAC allele frequencies of 0; no qualifying OR/RR and 95% CI were reported.
• The PS4 comparison direction is enrichment in affected individuals, and the governing threshold is OR or RR >5.0 with a confidence interval that does not include 1.0; no available source supplies both required components.

Still missing

• No qualifying case-control OR/RR with a 95% confidence interval excluding 1.0 was reported or calculable from the available counts.

Sources

Reasoning

The available patient descriptions involve dilated cardiomyopathy, conduction disease, ventricular arrhythmia, and related cardiac phenotypes. These findings are compatible with LMNA-related disease but are not highly specific for a disease with a single genetic etiology; the available cohort and family reports do not establish the required phenotype specificity.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Evidence considered

• PMID:11897440, Table 1/Family D: affected relatives had dilated cardiomyopathy and atrioventricular/conduction abnormalities, while some younger carriers had no cardiac signs at baseline.
• PMID:22199124, Results/Family A: the affected proband had syncope, conduction abnormalities, ventricular tachycardia, biventricular dysfunction, and sudden death; a carrier son had largely normal cardiac testing with brief NSVT.
• PMID:32041989, Results/Landscape of genetic alterations: the variant occurred in an idiopathic DCM cohort without variant-specific clinical details.

Still missing

• No highly specific phenotype or family-history pattern establishing a single genetic etiology was documented.

Sources

Reasoning

ClinVar reports the exact variant as Pathogenic with multiple submitters and a two-star review status, but the record contains no expert-panel classification. The available assertions are ordinary laboratory submissions or aggregate ClinVar results, which do not satisfy the required exact-variant expert-panel condition for PP5.

Rule

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar variation 66908 for NM_170707.4(LMNA):c.568C>T (p.Arg190Trp): aggregate classification Pathogenic, review status 'criteria provided, multiple submitters, no conflicts', review stars 2, with no expert-panel record; the listed submissions are clinical-laboratory assertions.

Still missing

• No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification was identified.

Sources

Reasoning

BS2 is not met. A son carrying LMNA p.Arg190Trp had a normal ECG and echocardiogram at age 25 but also had a short run of non-sustained ventricular tachycardia on 24-hour ECG, so he was not an unequivocally healthy adult. The family reports adult-onset disease and younger carriers without findings, indicating variable or age-dependent expression rather than the full early-age penetrance required by BS2. No homozygous or hemizygous observation is reported.

Rule

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Evidence considered

• PMID:22199124, Results Family A: the carrier son had normal ECG and echocardiogram but a short run of non-sustained ventricular tachycardia on 24-hour ECG; the paper also reports severe disease and sudden death in the mother.
• PMID:11897440, Family D: R190W carriers developed dilated cardiomyopathy and conduction disease in adulthood, while several younger carriers had no cardiac signs at baseline, supporting variable age-related expression rather than full early penetrance.

Sources

Reasoning

The variant is a missense substitution, so BP4 must be assessed through REVEL only; its SpliceAI result is not an alternative BP4 path, and BayesDel is not calibrated for generic ACMG strength. REVEL is 0.848, which is above the supplied BP4 supporting threshold of <=0.29 and therefore does not support a benign computational effect. BP4 is not met.

Rule

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• NM_170707.4:c.568C>T is a missense variant, so only REVEL applies for BP4; SpliceAI is not used for this missense path.
• Local REVEL lookup reports 0.848 for this variant (source_registry key: revel).
• REVEL 0.848 exceeds the supplied BP4 supporting threshold <=0.29; the generic ClinGen SVI calibration threshold is attributed in the governing prompt to Pejaver et al. 2022, PMID:36413997.
• SpliceAI returned no score and BayesDel has no established generic ACMG-strength calibration; neither can supply BP4 here.

Sources

Reasoning

No reviewed source reports this variant in a case where an alternate molecular basis for the disease was established. The available reports describe LMNA variant carriers and cardiac phenotypes, but do not document a confirmed alternative pathogenic molecular cause in the relevant case.

Rule

Variant found in a case with an alternate molecular basis for disease.

Evidence considered

• PMID:11897440: the report describes LMNA variants in familial DCM with atrioventricular block and does not identify an alternate molecular cause in the reported families.
• PMID:22199124: the report describes an LMNA variant in an ARVC-screened family and does not document a confirmed alternative pathogenic molecular basis for the affected proband.
• PMID:32041989: the cohort report lists p.R190W among LMNA variants in DCM patients but provides no alternate molecular diagnosis for the variant-positive patients.

Still missing

• No confirmed alternate molecular diagnosis was documented for a case carrying LMNA c.568C>T.

Sources

Reasoning

No exact-variant ClinVar expert-panel classification as Benign or Likely benign was identified. ClinVar instead shows an aggregate Pathogenic classification from multiple clinical laboratories without an expert-panel record, so BP6 cannot be applied.

Rule

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar variation 66908 for NM_170707.4(LMNA):c.568C>T (p.Arg190Trp): aggregate classification Pathogenic, review status 'criteria provided, multiple submitters, no conflicts', review stars 2, with no expert-panel record and no Benign or Likely benign expert-panel assertion.

Still missing

• No exact-variant ClinVar expert-panel Benign or Likely benign classification was identified.

Sources

Reasoning

No case-specific evidence establishes that LMNA c.568C>T arose de novo. The available reports describe familial cases and do not document confirmed maternity and paternity, parental genotypes, or absence of family history for the proband; therefore the PS2 definition cannot be applied.

Rule

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Evidence considered

• PMID:11897440 reports LMNA p.Arg190Trp in family D with familial autosomal-dominant dilated cardiomyopathy and atrioventricular block, not a confirmed de novo occurrence.
• PMID:22199124 reports the variant in Family A and in one son of an affected patient; it does not document parental testing establishing de novo status.
• PMID:32041989 explicitly reports no variant-specific segregation analysis or individual clinical details for p.R190W.

Still missing

• Confirmed maternity and paternity for the proband
• Both parents tested negative for LMNA c.568C>T
• Documented absence of relevant family history

Sources

Reasoning

The variant is LMNA NM_170707.4:c.568C>T (p.Arg190Trp). The reviewed literature reports clinical observations, rarity, conservation, and in-silico predictions, but no variant-specific in vitro or in vivo functional assay, assay controls, splicing experiment, or validated/reproducible diagnostic-laboratory functional result. The available evidence therefore does not establish the functional-study requirement for PS3, and it cannot be assigned from clinical observations or computational predictions alone.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• PMID:11897440, Results/Family D and Table 1: Arg190Trp was identified in a familial dilated-cardiomyopathy/atrioventricular-block cohort; the reported work used exon sequencing and clinical evaluation, not a functional assay.
• PMID:16537768: reviewed as a cited clinical-observation paper, but the available case evidence does not document a variant-specific functional assay for p.Arg190Trp.
• PMID:22199124, Results/Family A: c.568C>T (p.Arg190Trp) was reported with affected and carrier clinical observations; the study used sequencing, controls, and in-silico analyses rather than a functional assay.
• PMID:28416588: LMNA missense carriers were analyzed in a 152-patient dilated-cardiomyopathy cohort, but p.Arg190Trp was not specifically reported and no functional assay was provided.
• PMID:32041989, Results/Table 3: p.R190W was listed in a 118-patient dilated-cardiomyopathy cohort with computational scores, but no variant-specific functional assay or segregation analysis was reported.

Still missing

• A variant-specific, biologically relevant in vitro or in vivo assay with appropriate controls and validated/reproducible results is not available.

Sources

Reasoning

The available reports describe LMNA c.568C>T (p.Arg190Trp) in affected individuals and relatives, predominantly in autosomal-dominant dilated cardiomyopathy/conduction-disease families, but do not report a second pathogenic variant in the same individuals, parental testing, offspring testing establishing phase, or observation of this variant in trans with a pathogenic allele for a recessive LMNA disorder. The required allelic relationship for PM3 therefore cannot be assessed from the available evidence.

Rule

For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.

Evidence considered

• PMID:11897440, Results/Genetic studies and Table 1 Family D: R190W was reported in an autosomal-dominant dilated cardiomyopathy/conduction-disease family; the extracted report describes affected and younger carriers but no second pathogenic allele or phase result.
• PMID:22199124, Results Family A and Table 1: c.568C>T (p.Arg190Trp) was reported in an affected proband and an affected-risk son with a normal ECG/echocardiogram and brief NSVT; no second pathogenic variant or trans-phase result was reported.
• PMID:32041989, Results and Table 3: p.R190W was reported in two unrelated DCM patients, with no variant-specific segregation analysis, second pathogenic allele, or phase information.

Still missing

• A second pathogenic or likely pathogenic LMNA variant in the same affected individual has not been documented.
• Parental or offspring testing establishing trans phase has not been documented.
• The relevant recessive LMNA disease context for any putative compound-heterozygous observation is not documented.

Sources

Reasoning

The available evidence confirms the observed p.Arg190Trp variant but does not identify a different missense substitution at Arg190 that was independently established as pathogenic. The collected PM5 candidate summary contains zero same-residue candidates, and no qualifying comparator can be verified from the available paper extracts.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Evidence considered

• The PM5 candidate summary reports zero collected same-residue candidates and explicitly does not establish classic PM5 semantics; this is insufficient to conclude that no comparator exists.

Still missing

• A verified pathogenic missense comparator at residue Arg190.

Sources

Reasoning

No case-specific evidence establishes an assumed de novo LMNA c.568C>T occurrence. The available reports do not provide a proband-specific parental genotype assessment or a documented de novo event without parental confirmation, so PM6 cannot be applied.

Rule

Assumed de novo, but without confirmation of paternity and maternity.

Evidence considered

• PMID:11897440 describes familial autosomal-dominant disease with p.Arg190Trp in family D rather than an assumed de novo occurrence.
• PMID:22199124 describes transmission of the variant to a son and provides no proband-specific parental testing establishing assumed de novo status.
• PMID:32041989 reports no variant-specific segregation analysis for p.R190W.

Still missing

• A documented de novo occurrence in the proband
• Parental testing status showing that maternity and/or paternity was not confirmed

Sources

Reasoning

The available case evidence does not establish both required gene-level conditions: a low rate of benign missense variation and missense variants being a common disease mechanism for LMNA. One cohort paper reports six LMNA missense carriers and one truncating carrier, but that limited cohort observation is not a gene-wide benign-missense rate or a validated disease-mechanism estimate.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

Evidence considered

• Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy, Methods/Results: reports seven LMNA carriers, comprising one truncating and six missense variants, but does not provide the gene-wide benign-missense rate or establish missense as the common disease mechanism.

Still missing

• Gene-wide evidence for a low benign-missense rate and for missense as a common LMNA disease mechanism.

Sources

Reasoning

BA1 was not assessed as a stand-alone benign call. gnomAD v4.1 reports total AF 6.195640994821683e-07 (1/1,614,038 alleles), far below the generic >=0.05 threshold, and grpmax FAF is unavailable. The only higher ancestry-specific point estimate is Amish AF 0.0010964912280701754 from 1/912 alleles, below the required 2,000 observed-allele minimum for filtering-frequency use. The variant also has a pathogenic ClinVar consensus, so the available data do not justify ending classification with BA1.

Rule

BA1

Evidence considered

• gnomAD v4.1: total AF 6.195640994821683e-07, 1/1,614,038 alleles; grpmax FAF is null.
• gnomAD v4.1: Amish point-estimate AF 0.0010964912280701754, 1/912 alleles; this population is below the 2,000 observed-allele minimum for BA1/BS1 filtering-frequency use.
• Generic calibration threshold: BA1 >=0.05, ACMG/AMP 2015 stand-alone benign allele-frequency threshold (PMID:25741868).
• ClinVar variation 66908: Pathogenic, criteria provided, multiple submitters, no conflicts; this conflicts with an automatic stand-alone benign interpretation.

Still missing

• A valid gnomAD filtering allele frequency (grpmax FAF) from a population with at least 2,000 observed alleles is unavailable.

Sources

Reasoning

BS1 was not assessed. The all-comers gnomAD v4.1 total AF is 6.195640994821683e-07, below the generic 0.01 default, but the required filtering allele frequency, grpmax FAF, is unavailable. The Amish point estimate of 0.0010964912280701754 is based on only 1/912 alleles and cannot be used under the 2,000 observed-allele minimum. No disease-specific maximum-credible-frequency calculation with explicit prevalence, penetrance, and allelic-heterogeneity inputs is available; therefore the ancestry-specific point estimate cannot establish BS1.

Rule

BS1

Evidence considered

• gnomAD v4.1: total AF 6.195640994821683e-07; grpmax FAF is null.
• gnomAD v4.1: Amish point-estimate AF 0.0010964912280701754 (0.10965%), 1/912 alleles; the population is below the 2,000 observed-allele minimum.
• Generic BS1 default threshold: >=0.01. Maximum credible allele frequency should be considered using Whiffin et al. 2017 (PMID:28518168), but disease-specific prevalence, penetrance, and allelic-heterogeneity inputs are not available.

Still missing

• A valid grpmax FAF from a population with at least 2,000 observed alleles is unavailable.
• A maximum-credible-frequency calculation with explicit disease prevalence, penetrance, and allelic-heterogeneity inputs is unavailable.

Sources

Reasoning

The reviewed evidence does not include a variant-specific in vitro or in vivo study showing no damaging effect on LMNA protein function or splicing. The clinical reports and computational predictions for p.Arg190Trp neither demonstrate preserved function nor provide validated assay controls or reproducible diagnostic-laboratory functional results. BS3 therefore cannot be assigned.

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• PMID:11897440: the paper reports clinical and sequence-based observations for Arg190Trp but no assay demonstrating absence of a damaging effect.
• PMID:16537768: reviewed for functional evidence; the available report does not provide a variant-specific assay showing preserved LMNA function or splicing.
• PMID:22199124: the study reports clinical observations, population controls, and in-silico analyses for p.Arg190Trp, not a normal-function or normal-splicing assay.
• PMID:28416588: the cohort paper does not specifically report p.Arg190Trp and provides no assay evidence for preserved function.
• PMID:32041989: computational scores and cohort listing do not demonstrate no damaging effect and no functional or splicing assay was reported.

Still missing

• A well-established variant-specific assay demonstrating preserved LMNA protein function or normal splicing is not available.

Sources

Reasoning

The available reports do not identify affected family members who lack LMNA c.568C>T. PMID:22199124 describes an unaffected young carrier, and PMID:11897440 describes younger carriers without baseline signs, but these are not affected non-carriers and therefore do not establish lack of segregation among affected members. No BS4 evidence can be assigned.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• PMID:11897440 reports younger R190W carriers without cardiac signs at baseline, which is not lack of segregation in affected members.
• PMID:22199124 reports one 25-year-old R190W carrier with normal ECG and echocardiogram but a short run of NSVT; this is an unaffected carrier, not an affected non-carrier.
• No reviewed source documents an affected relative who tested negative for LMNA c.568C>T.

Still missing

• Genotypes and disease phenotypes for affected relatives who do not carry LMNA c.568C>T
• Pedigree-level assessment excluding phenocopies or multiple pathogenic variants

Sources

Reasoning

The available evidence does not establish that LMNA disease is caused primarily by truncating variants. The cited cohort actually reports one truncating and six missense LMNA carriers, but this is not sufficient to characterize the gene-wide disease spectrum or exclude a substantial missense mechanism.

Rule

Missense variant in a gene for which primarily truncating variants are known to cause disease.

Evidence considered

• Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy, Methods/Results: reports one truncating and six missense LMNA carriers, which does not support a primarily truncating mechanism but is insufficient for a definitive gene-wide conclusion.

Still missing

• Gene-wide variant-spectrum evidence showing that LMNA disease is primarily caused by truncating variants.

Sources

Reasoning

The available literature reports this variant in affected individuals and relatives but does not document the variant in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. No phase-resolved second pathogenic allele is reported, so BP2 cannot be assessed.

Rule

Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• PMID:11897440, Results/Genetic studies and Table 1 Family D: the paper reports R190W in an autosomal-dominant family but does not report a pathogenic variant in cis or trans or molecular phase testing.
• PMID:22199124, Results Family A and Table 1: the paper reports the same variant in a proband and her son, without a second pathogenic variant or cis/trans phase determination.
• PMID:32041989, Results and Table 3: p.R190W was reported in two unrelated DCM patients, without a second pathogenic variant or phase information.

Still missing

• No documented trans observation with a pathogenic variant in a fully penetrant dominant disorder.
• No documented cis observation with a pathogenic variant.
• No parental, offspring, or other molecular phase testing is reported.

Sources