The PCSK9 NM_174936.4:c.137G>T (NP_777596.2:p.(Arg46Leu)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be Benign.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.PCSK9 encodes a protein that helps regulate cholesterol levels by directing certain cholesterol-carrying receptors to be broken down, especially in the liver. Changes in this gene can cause autosomal dominant familial hypercholesterolemia, an inherited condition involving abnormally high blood cholesterol. PCSK9 has no established role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Met: gnomAD v4.1 grpmax FAF is 1.65%, above the 1% BS1 threshold, using a population with 61,024 observed alleles.
Met: gnomAD v4.1 contains 226 homozygotes, and ARIC reported eight adult white homozygotes for PCSK9 R46L.
Met, supporting: REVEL 0.028 is below the <=0.29 BP4 threshold for this missense variant.
Benign: BS1 (strong) and BS2 (strong) satisfy the generic ACMG/AMP rule for two strong benign criteria, with BP4 (supporting) also applied.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 23,500 / 1,580,590 alleles. Recorded AF 0.0148679. Recorded homozygote count 226.
This variant is present in gnomAD v2.1 (AF= 0.0122221; MAF= 1.22221%, 2782/227620 alleles, homozygotes = 37) and has highest observed frequency in the European (Finnish) population (AF= 0.0425861; MAF= 4.25861%, 880/20664 alleles, homozygotes = 25); grpmax FAF= 0.0144002.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.028. Refer to the recorded PP3/BP4 rationale for interpretation.
12 Benign · 3 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 11 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The queried variant is PCSK9 NM_174936.4:c.137G>T, p.Arg46Leu, a common population allele with benign/likely benign ClinVar submissions and published associations with reduced LDL cholesterol.
No qualifying same-amino-acid pathogenic variant, different pathogenic variant at residue 46, hotspot, or critical-domain evidence was identified for PS1, PM1, or PM5.
PCSK9's observed missense variation and recognized gain-of-function missense mechanism do not support PP2 or BP1.
No case-level proband, parental-testing, pedigree, affected-relative segregation, or non-segregation evidence was available for PS2, PM6, PP1, or BS4; all four criteria are therefore not assessed.
No VCEP covers PCSK9 in this case; generic ACMG/AMP rules govern.
The exact-variant literature reviewed for PS4 shows protective or non-enriching associations rather than the required affected-case enrichment.
PP5 and BP6 are not triggered because ClinVar has no exact-variant expert-panel classification.
Generic ACMG/AMP rules govern because no VCEP covers PCSK9.
The variant is missense, so PP3 and BP4 use exactly one computational path: REVEL; the REVEL result supports BP4 at supporting strength and does not meet PP3.
SpliceAI and BayesDel were not double-counted or substituted into the missense REVEL assessment.
Population evidence supports a benign interpretation for PCSK9 c.137G>T (p.Arg46Leu): BA1 is not met because grpmax FAF is below 5%, but BS1 and BS2 are met and PM2 is not met.
The assessment uses gnomAD filtering grpmax FAF rather than popmax point estimates and does not apply a non-cancer or exome-only subset because no governing VCEP-specific source rule is present.
No criteria match.
BS1 is met. The applicable filtering metric is grpmax FAF, and the relevant population allele counts exceed 2000: gnomAD v4.1 grpmax FAF=0.0164944 and gnomAD v2.1 grpmax FAF=0.0144002, both above the generic BS1 default of >=0.01. The elevated frequency is not restricted to a small isolate group, and the evidence concerns PCSK9 p.Arg46Leu, a loss-of-function allele, whereas familial hypercholesterolemia due to PCSK9 is associated with gain-of-function; the observed frequency is therefore greater than expected for a pathogenic PCSK9-FH allele. Finnish popmax point estimates were not used.
Allele frequency is greater than expected for the disorder.
BS2 is met. The variant is observed in healthy population adults in the relevant dominant PCSK9 familial-hypercholesterolemia context, including 226 homozygotes in gnomAD v4.1 and 37 homozygotes in gnomAD v2.1. Independently, the ARIC adult cohort reported eight white participants homozygous for PCSK9 137G>T/R46L. Such repeated homozygosity in adult population cohorts is incompatible with a fully penetrant early-onset dominant disease allele. The population data are supported by the exact-variant ARIC report, which describes R46L as common and associated with lower LDL cholesterol.
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.
The variant is a missense change, NM_174936.4:c.137G>T (NP_777596.2:p.(R46L)), so the governing generic rule selects the REVEL path only; the splice predictor is not used for BP4. REVEL is 0.028, which is below the supporting BP4 threshold of <= 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). Therefore BP4 is met at supporting strength.
BP4: 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) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
PS1 is not met. The variant is NM_174936.4:c.137G>T, NP_777596.2:p.(Arg46Leu), and the reviewed exact-variant evidence describes R46L as a low-frequency loss-of-function allele associated with lower LDL cholesterol and reduced coronary risk, not as a previously established pathogenic variant. No different nucleotide change producing the same Arg46Leu substitution was identified as an established pathogenic variant.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Generic ACMG/AMP PS4 requires significant enrichment of the exact variant in affected individuals versus controls, with OR or RR >5.0 and a confidence interval excluding 1.0. PMID:16554528 directly studied PCSK9 137G>T (R46L) in ARIC and reported CHD events in 19/301 carriers versus 1089/9223 noncarriers. Treating CHD events as the affected group, I computed the unadjusted case-control OR as (19/282)/(1089/8134) = 0.503, with an approximate 95% CI of 0.315–0.804; the required comparison is 0.503 > 5.0? no, although the CI excludes 1.0. Thus the observed direction is protective rather than enriched and PS4 is not met. The required AI-classified PS4 paper, PMID:33091218, was verified against full text: it identified the exact R46L variant and reported protective associations with NAFLD, NASH, and fibrosis (NAFLD OR 0.42, 95% CI 0.22–0.81), not pathogenic-phenotype enrichment.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: 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.
PM1 is not met. No PCSK9 VCEP specification or authoritative domain table is available for this case, the Cancer Hotspots search reports no statistically significant hotspot at the queried R46 position, and the supplied evidence does not establish Arg46 as part of a critical and well-established functional domain without benign variation. The variant is therefore not assigned PM1 under the generic 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.
PM2 is not met. The variant is common in the applicable all-comers gnomAD datasets: gnomAD v4.1 reports AF=0.0148679 and gnomAD v2.1 reports AF=0.0122221. These values are far above the generic PM2 supporting threshold of <=0.0001, and the variant has numerous homozygotes (226 in v4.1; 37 in v2.1). No VCEP rule requires a non-cancer or exome-only subset for this generic assessment.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PM5 is not met. The variant is the missense substitution p.Arg46Leu, but the supplied same-residue comparator collection contains zero candidates and identifies no different missense variant at residue 46 that has been determined to be pathogenic. The exact variant's benign/low-LDL evidence cannot satisfy PM5 because PM5 requires a different pathogenic missense change at the same amino-acid residue.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PP2 is not met. The required combination is not supported: PCSK9 is described as relatively polymorphic, with 52% of 113 familial-hypercholesterolemia-associated PCSK9 variants being missense, and the queried R46L allele is common in population data (gnomAD v4.1 allele frequency 0.0148679; Finnish frequency 0.0392305). These data do not support a low rate of benign missense variation. Although PCSK9 gain-of-function missense variants are a recognized disease mechanism, the first PP2 requirement is not satisfied.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The variant is a missense change, NM_174936.4:c.137G>T (NP_777596.2:p.(R46L)), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3. REVEL is 0.028, which is below the supporting PP3 threshold of >= 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). Therefore PP3 is not met.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation 2878 has zero expert-panel submissions and instead contains ordinary laboratory submissions, with aggregate Benign/Likely benign labels and one non-criteria Pathogenic submission; these cannot trigger PP5.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. ... Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.
BA1 is not met. With no VCEP-specific population source, the all-comers gnomAD data are applicable. The required filtering frequency is the grpmax FAF, not the Finnish popmax point estimate: gnomAD v4.1 reports grpmax FAF=0.0164944 and gnomAD v2.1 reports grpmax FAF=0.0144002, both below the generic BA1 threshold of >=0.05. The Finnish popmax values (0.0392305 in v4.1 and 0.0425861 in v2.1) are not used for BA1, and the relevant population allele counts exceed 2000. The variant is also a well-established common PCSK9 p.Arg46Leu loss-of-function allele with a benign ClinVar consensus, so there is no frequency-versus-pathogenic-consensus conflict requiring BA1 to be marked not_assessed.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BP1 is not met. The supplied gene-level evidence identifies PCSK9 gain-of-function mutations, including missense disease mechanisms for familial hypercholesterolemia, rather than showing that disease is caused primarily by truncating variants. Therefore this missense variant does not meet the BP1 gene-mechanism premise.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar variation 2878 has zero expert-panel submissions; its Benign/Likely benign results are ordinary laboratory submissions and an aggregate label, so BP6 cannot be applied under the stated rule.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. ... Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.
PS2 cannot be assessed because the available case evidence does not document a proband with the relevant disease phenotype and no family history together with confirmed maternity and paternity and a de novo variant observation. No proband-level pedigree, parental genotypes, or maternity/paternity confirmation is provided.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The available exact-variant publications report human genetic associations for PCSK9 p.R46L, including lower LDL cholesterol, but do not provide a validated in vitro or in vivo assay directly testing the variant's damaging effect on PCSK9 function. The available extraction for PMID:33091218 explicitly states that it does not provide direct experimental evidence specifically for the R46L mechanism. Therefore, the evidence is insufficient to assess PS3 rather than to call it not met.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM6 cannot be assessed because the available case evidence does not document an assumed de novo variant in the proband. There are no reported parental genotypes or other case-level observations establishing that the variant was absent from the parents, whether or not maternity and paternity were confirmed.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed because no affected family members, family structure, variant genotypes, phenotype assessments, or informative meioses are documented. The available literature concerns population-level studies of PCSK9 p.R46L and does not provide segregation of this variant with disease in multiple affected relatives.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
PP4 requires a patient phenotype or family history that is highly specific for a disease with a single genetic etiology. The available case materials identify the PCSK9 variant but provide no patient phenotype, clinical presentation, or family-history description, so specificity cannot be judged.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The available exact-variant publications do not establish absence of a damaging effect through a well-established functional assay. Human association findings for PCSK9 p.R46L and measurements of metabolic traits do not constitute direct evidence that the protein has no damaging functional effect, and the available extraction for PMID:33091218 explicitly notes no direct experimental evidence for the variant's mechanism. Therefore, BS3 cannot be assessed.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BS4 cannot be assessed because no affected family members are identified with genotype and phenotype results showing that the variant fails to segregate with disease. The available case evidence contains no pedigree, non-segregation observations, or information sufficient to exclude phenocopies or another pathogenic variant in the family.
Lack of segregation in affected members of a family.
The available evidence does not document this variant observed in trans with a pathogenic variant in an affected individual with a fully penetrant dominant disorder, nor observed in cis with a pathogenic variant. Population homozygote counts and functional or association studies do not establish the required allelic phase or a pathogenic partner variant. Therefore BP2 cannot be assessed.
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.
BP5 requires the variant to be found in a case with an alternate molecular basis for disease. The available evidence contains no case-level alternate pathogenic molecular diagnosis or documented alternative genetic cause, so BP5 cannot be assessed.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_174936.4:c.137G>T in PCSK9 is a missense substitution predicted to produce NP_777596.2:p.(Arg46Leu). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for PCSK9, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is not applicable because the case evidence identifies the relevant PCSK9 familial hypercholesterolemia context as autosomal dominant, whereas PM3 is restricted to recessive disorders and requires the tested variant to be in trans with a pathogenic variant. No recessive inheritance context is established for this variant.
For recessive disorders, detected in trans with a pathogenic variant
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_174936.4:c.137G>T in PCSK9 is a missense substitution predicted to produce NP_777596.2:p.(Arg46Leu). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for PCSK9, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_174936.4:c.137G>T in PCSK9 is a missense substitution predicted to produce NP_777596.2:p.(Arg46Leu). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for PCSK9, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_174936.4:c.137G>T in PCSK9 is a missense substitution predicted to produce NP_777596.2:p.(Arg46Leu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PCSK9, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in PCSK9, mapped onto the exon structure of NM_174936.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (Finnish)2394 / 61,024 | 0.03948 hom |
| European (non-Finnish)19432 / 1,164,182 | 0.017159 hom |
| Remaining individuals813 / 61,242 | 0.01312 hom |
| Admixed American406 / 55,508 | 0.00733 hom |
| Amish6 / 912 | 0.0066 |
| Ashkenazi Jewish147 / 28,948 | 0.0051 |
| Middle Eastern26 / 5,138 | 0.00511 hom |
| African/African American184 / 74,402 | 0.00252 hom |
| South Asian92 / 86,168 | 0.00111 hom |
| European (Finnish)880 / 20,664 | 0.04325 hom |
| European (non-Finnish)1501 / 99,592 | 0.01510 hom |
| Remaining individuals82 / 6,228 | 0.013 |
| Admixed American193 / 30,198 | 0.00641 hom |
| Ashkenazi Jewish44 / 9,332 | 0.0047 |
| African/African American53 / 20,270 | 0.00261 hom |
| South Asian29 / 25,034 | 0.0012 |
This variant is present in gnomAD v4.1 (AF= 0.0148679; MAF= 1.48679%, 23500/1580590 alleles, homozygotes = 226) and has highest observed frequency in the European (Finnish) population (AF= 0.0392305; MAF= 3.92305%, 2394/61024 alleles, homozygotes = 48); grpmax FAF= 0.0164944.
This variant is present in gnomAD v2.1 (AF= 0.0122221; MAF= 1.22221%, 2782/227620 alleles, homozygotes = 37) and has highest observed frequency in the European (Finnish) population (AF= 0.0425861; MAF= 4.25861%, 880/20664 alleles, homozygotes = 25); grpmax FAF= 0.0144002.
Not available in gnomAD-Canada v1.0.
The variant is a missense change, NM_174936.4:c.137G>T (NP_777596.2:p.(R46L)), so the governing generic rule selects the REVEL path only; the splice predictor is not used for BP4. REVEL is 0.028, which is below the supporting BP4 threshold of <= 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). Therefore BP4 is met at supporting strength.
BP4: 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) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The variant is a missense change, NM_174936.4:c.137G>T (NP_777596.2:p.(R46L)), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3. REVEL is 0.028, which is below the supporting PP3 threshold of >= 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). Therefore PP3 is not met.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_174936.4:c.137G>T in PCSK9 is a missense substitution predicted to produce NP_777596.2:p.(Arg46Leu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PCSK9, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.028. BayesDel score = -0.529793.
8 paper records listed. 1 cited in the classification.
We also identified a PCSK9 sequence variation (137G→T, encoding R46L [replacement of the arginine at position 46 with leucine]) that is more common among white subjects (prevalence, 3.2 percent) than among black subjects (0.6 percent) and that is associated with a 21 percent decrease in plasma LDL cholesterol levels.
Location Introduction, page 1265; Results, pages 1268–1269; Table 2
Context ARIC prospective cohort study; 9524 white and 25 heterozygous black participants were analyzed for the R46L allele, with TaqMan genotyping and coronary outcomes followed for approximately 15 years.
Significant associations (p<10−6) were found between p.R46L and lower total cholesterol (−0.394 mmol/l), LDL-cholesterol (−0.393 mmol/l) and apolipoprotein B concentrations (−0.099 g/l). However, no significant association was observed between p.R46L and markers of glucose homeostasis
Abstract; Results, first and third paragraphs; Tables 1 and 2
Functional studies are of even greater importance for APOB and PCSK9 genes, which are more polymorphic than LDLR.
Results, ‘Variant analysis’ and ‘Variants with functional studies’; Discussion
Genotyping for PNPLA3 (rs738409 C>G), TM6SF2 (rs58542926 C>T), and PCSK9 (rs11591147 G>T; R46L)was carried out using the TaqMan SNP genotyping allelic discrimination method.
Genetic Analyses; Results, Human Data; Discussion
Gain-of-function mutations in PCSK9 cause fewer than 5% of cases in most studies.
Section 1.3, Genetics of FH, recommendation 1.3.4
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.0148679; MAF= 1.48679%, 23500/1580590 alleles, homozygotes = 226) and has highest observed frequency in the European (Finnish) population (AF= 0.0392305; MAF= 3.92305%, 2394/61024 alleles, homozygotes = 48); grpmax FAF= 0.0164944.
This variant is present in gnomAD v2.1 (AF= 0.0122221; MAF= 1.22221%, 2782/227620 alleles, homozygotes = 37) and has highest observed frequency in the European (Finnish) population (AF= 0.0425861; MAF= 4.25861%, 880/20664 alleles, homozygotes = 25); grpmax FAF= 0.0144002.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Benign (12 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 2878)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.028. BayesDel score = -0.529793.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.