The LDLR NM_000527.5:c.1775G>A (NP_000518.1:p.(Gly592Glu)) missense variant has previously been reported in somatic cancers (COSMIC; COSV52945923, n = 1 time). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel; ClinVar ID 161271).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.LDLR encodes a cell-surface receptor that removes low-density lipoprotein (LDL) and cholesterol from the bloodstream into cells, helping regulate cholesterol levels and synthesis. Inherited defects in LDLR cause familial hypercholesterolemia, an autosomal dominant disorder characterized by abnormally high cholesterol. LDLR is not known to have a direct cancer association.
The recorded framework is ClinGen LDLR VCEP v1.2. 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.
Met at Moderate: gnomAD v4.1 PopMax FAF is 0.00004863 (0.004863%), below the VCEP's <=0.0002 (0.02%) threshold.
Met at Supporting: REVEL score 0.938 meets the VCEP PP3 missense threshold of >=0.75.
Not applicable: the FH VCEP explicitly excludes PP5, regardless of reported pathogenic classifications.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 (moderate) plus PP3 and PP5 (supporting) do not satisfy an ACMG/AMP 2015 pathogenic or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 75 / 1,613,914 alleles. Recorded AF 4.64709e-05. Recorded homozygote count 2.
This variant is present in gnomAD v2.1 (AF= 5.65639e-05; MAF= 0.00566%, 16/282866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000116121; MAF= 0.01161%, 15/129176 alleles, homozygotes = 0); grpmax FAF= 0.00012682.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.938. Refer to the recorded PP3/BP4 rationale for interpretation.
33 Pathogenic · 4 Likely pathogenic · 1 pathogenic. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV52945923, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen LDLR VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 5 not met · 13 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
None of PS2, PM6, PP1, or BS4 can be assigned from the available patient-specific parental, family-segregation, or non-segregation evidence under the ClinGen FH VCEP specifications.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
PS4 and PP4 were not assessed because the available clinical reports do not document the VCEP-required validated FH diagnostic criteria and, for PP4, exclusion of alternative causes.
No case-control comparison was reported in the reviewed PS4 literature; therefore no odds ratio or confidence interval was fabricated or inferred from an unmatched aggregate population frequency.
The VCEP's computational rules were settled before using predictor values: PP3 and BP4 name REVEL for missense variants and MaxEntScan for splice prediction; BP7 is limited to synonymous variants and requires BP4.
PP3 is met because the VCEP-named missense predictor REVEL is 0.938, above the VCEP threshold of 0.75.
BP4 is not assessed because REVEL is above its <=0.5 threshold and no VCEP-named MaxEntScan result is available; SpliceAI is not substituted.
BP7 is not applicable because the variant is missense, not synonymous.
The four requested criteria were evaluated only under the ClinGen Familial Hypercholesterolemia Expert Panel Version 1.2 rules. Population frequency supports PM2 at Moderate strength, while the observed frequency is below the BA1 and BS1 thresholds; BS2 remains not assessed because the required normolipidemic adult phenotyping is unavailable.
No criteria match.
The governing VCEP applies PM2 at Moderate strength when the variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD, with consideration of exceptions for known founder variants. gnomAD v4.1 reports a maximum population frequency/PopMax FAF of 0.00004863 (0.004863%), which is below 0.0002. No governing-rule exception for this variant is documented. PM2 is met at Moderate strength.
Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.
NM_000527.5:c.1775G>A is a missense variant producing NP_000518.1:p.(Gly592Glu). The governing VCEP PP3 rule names REVEL >=0.75 for missense variants, or predicted splicing using MaxEntScan. The available REVEL score is 0.938, which meets the VCEP's missense threshold, so PP3 is met at Supporting strength. The available SpliceAI score was not used because SpliceAI is not the predictor named by this VCEP rule for the splicing pathway.
REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
Expert panel ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP limits PM1 to a missense variant in exon 4 or a missense change in one of 60 highly conserved cysteine residues, and requires PM2. This variant is missense in exon 12 at Gly592, not exon 4 and not a cysteine residue. Its gnomAD v4.1 PopMax FAF is 0.00004863, which satisfies the PM2 caveat, but the PM1 location requirement is not met. vcep_materials.json has no LDLR domain-table entry providing an additional approved domain route.
Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2.
PM4 is not met. NM_000527.5:c.1775G>A is a single-nucleotide missense substitution producing p.(Gly592Glu), not an in-frame deletion or insertion smaller than one whole exon and not an in-frame whole-exon duplication. The VCEP PM4 caveat also requires PM2; that prerequisite is satisfied because the gnomAD v4.1 PopMax FAF is 0.00004863, below the VCEP PM2 threshold of 0.0002, but the required protein-length-change type is absent.
In-frame deletion/insertions smaller than one whole exon, or in-frame whole-exon duplications not considered in any PVS1 criteria. Caveat: variant must also meet PM2.
The governing VCEP applies BA1 when the variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD. The highest observed gnomAD v4.1 population frequency is the European (non-Finnish) PopMax/maximum group frequency, FAF 0.00004863 (0.004863%; 71/1,179,988 alleles), which is below 0.005. Therefore BA1 is not met.
Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.
The governing VCEP applies BS1 when the variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD. The highest observed gnomAD v4.1 population frequency is PopMax FAF 0.00004863 (0.004863%), below 0.002. Therefore BS1 is not met.
Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.
The VCEP BS3 rules require a qualifying benign study showing either >90% of wild-type activity for expression/biosynthesis, binding, and internalization in a heterologous-cell whole-cycle assay, or the specified Level 3 benign alternatives. PMID:1301956 instead reports <2% of control LDLR activity for the exact variant in fibroblast assays, with no evidence of preserved activity across all three LDLR-cycle components. Thus the available functional evidence does not meet BS3; the study's design limitations also warrant human review.
Variant meets Level 1 benign functional study criteria. See Table 3. (1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization. Note: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting.
The LDLR variant is p.Gly592Glu and has an expert-panel Pathogenic ClinVar record, but the available evidence does not identify a different nucleotide change at the same codon that is independently classified pathogenic. The VCEP also requires no predicted splicing impact for both variants; no comparator variant is available to evaluate that requirement.
Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change. ... Caveat: there is no in silico predicted splicing impact for either variant.
The VCEP requires a de novo variant in a patient with the disease and no family history. The available case evidence identifies affected FH cohorts and variant carriers but provides no patient-specific parental testing, confirmation of maternity and paternity, or documented absence of family history; therefore PS2 cannot be evaluated.
PMID:1301956 reports the exact mature-protein equivalent G571E (precursor p.Gly592Glu) with LDLR activity <2% of control in patient fibroblast assays measuring 125I-LDL degradation and LDL-mediated cholesteryl-ester formation. This is damaging functional evidence, but the available record does not establish the VCEP Level 1 heterologous-cell/no-endogenous-LDLR whole-cycle design, nor does it establish that the tested cells were true homozygous patient cells as required for the Level 2 patient-cell pathway; it also does not provide the complete assay components and controls needed to assign a VCEP PS3 strength. Therefore PS3 is not assessed rather than calibrated from a generic functional rule.
Variant meets Level 2 pathogenic functional study criteria. See Table 3. (1) Study of a) only part of the LDLR cycle following Level 1 methodology, or b) whole or part of the LDLR cycle in true homozygous patient cells. A variant with assay results of <70% of wild type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.
The VCEP provides Supporting, Moderate, and Strong paths requiring respectively 2-5, 6-9, or >=10 unrelated FH cases with FH diagnosis met by validated clinical criteria, plus PM2. PMID:11317361 directly reports the exact variant under the equivalent G1775A/G571E notation in 21 of 73 unrelated clinically diagnosed FH patients, and the literature-pass classifier reports 38 of 378 unrelated clinically diagnosed patients in PMID:20145306. The count comparisons are 21 >= 10? yes and 38 >= 10? yes, but the available evidence does not document that the diagnostic criteria were validated, so the VCEP Strong path cannot be confirmed. No unaffected or population-control comparison was reported in the reviewed case-series evidence; therefore no case-control odds ratio or 95% confidence interval can be calculated from those papers. The variant meets the PS4 caveat's PM2 population-frequency condition: gnomAD v4.1 PopMax FAF 0.00004863 <= 0.0002? yes.
Variant is found in ≥10 unrelated FH cases (FH diagnosis met by validated clinical criteria). Caveat: variant must also meet PM2... Variant is found in 6-9 unrelated FH cases (FH diagnosis made by validated clinical criteria). Caveat: variant must also meet PM2. ... Variant is found in 2-5 unrelated FH cases (FH diagnosis made by validated clinical criteria). Caveat: variant must also meet PM2.
The ClinGen FH VCEP permits PM3 at Moderate strength only when a candidate LDLR variant is observed in an individual with a homozygous FH phenotype and there is only one other pathogenic or likely pathogenic variant in LDLR in trans, APOB or PCSK9; the candidate must also meet PM2. PMID:11317361 reports c.1775G>A in five homozygous patients, but the available evidence does not identify a single additional pathogenic or likely pathogenic variant in the patient(s), establish its identity, or document phase in trans. The PM2 prerequisite is supported by the gnomAD v4.1 PopMax FAF of 0.00004863, below the VCEP threshold of 0.0002. Therefore PM3 cannot be adjudicated from the available phase and second-variant data.
This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2.
The VCEP permits PM5 at moderate strength when a missense variant is at the same codon as a pathogenic variant predicting a different amino acid. The collected PM5 search found no same-residue comparator candidates, and the search also reported an HTTP 429 failure; therefore the available evidence cannot establish whether a qualifying pathogenic comparator exists.
Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.
The VCEP assigns PM6 to the PS2 pathway, which requires evaluation of a de novo occurrence without the necessary evidence for PS2. No patient-specific parental testing, confirmed maternity and paternity, or documented de novo observation is available, so PM6 cannot be evaluated.
The VCEP requires 2-3 informative meioses with at least one affected relative above the LDL-C 75th centile for supporting PP1, with higher strengths requiring more specified meioses and affected relatives. The reviewed variant reports describe FH carriers and cohort frequencies but provide no family-specific informative meioses, LDL-C centiles, or segregation results.
The VCEP PP4 Supporting rule requires an LDLR variant in an FH patient whose diagnosis is based on validated criteria such as Dutch Lipid Clinic Network >=6, Simon Broome possible/definite, or MEDPED, after alternative causes of high cholesterol are excluded, and also requires PM2. The available reports identify the variant in clinically diagnosed FH cohorts, but do not provide a qualifying validated diagnostic score/category and do not document exclusion of alternative causes. The PM2 condition is supported because gnomAD v4.1 PopMax FAF 0.00004863 <= 0.0002? yes.
Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded. Caveat: variant must also meet PM2.
The governing VCEP requires the variant to be identified in at least 3 heterozygous or at least 1 homozygous well-phenotyped, untreated, normolipidemic unrelated adult. gnomAD v4.1 reports 2 homozygotes, but provides no evidence that they are well-phenotyped, untreated, normolipidemic adults and does not establish the required unrelated adult observations. The available literature describes homozygous familial-hypercholesterolemia patients, not qualifying normolipidemic adults. The BS2 rule therefore cannot be evaluated from the available evidence.
Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated).
The VCEP requires lack of segregation in at least two unrelated index-case families, at least two informative meioses in each family, and at least one unaffected relative below the LDL-C 50th centile who carries the variant. No such non-segregation families, meioses, unaffected carrier, or LDL-C centile data are available.
The ClinGen FH VCEP permits BP2 at Supporting strength only if an FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR in trans, APOB or PCSK9, with the candidate being an additional LDLR variant. The available case evidence does not document a qualifying additional LDLR, APOB, or PCSK9 variant, nor does it establish trans phase or the required heterozygous phenotype. BP2 is therefore not assessed.
If a FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9, BP2 is applicable to any additional LDLR variants.
NM_000527.5:c.1775G>A is a missense variant, so the VCEP BP4 missense pathway is in scope. The governing rule requires REVEL <=0.5 for the missense pathway, or no predicted impact to splicing using MaxEntScan. The available REVEL score is 0.938 and therefore does not meet the BP4 REVEL threshold. No MaxEntScan result is available, and the available SpliceAI result cannot substitute because SpliceAI is not the predictor named by the VCEP rule. BP4 therefore cannot be assessed from the available governing-rule evidence.
REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
PVS1 is not applicable. The variant is NM_000527.5:c.1775G>A (NP_000518.1:p.(Gly592Glu)), a missense substitution in exon 12 of the preferred transcript, not a nonsense, frameshift, canonical splice-site, initiation-codon, or single/multi-exon deletion variant. The VCEP PVS1 rule limits this criterion to null variant classes; therefore no NMD, exon-importance, protein-length, or repeat-region downgrade pathway applies.
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
The LDLR VCEP marks PP2 as not applicable for this VCEP, so the generic missense-mechanism rule is not used.
Not Applicable for this VCEP
The LDLR VCEP marks BP1 as not applicable for this VCEP, so the generic benign missense-in-a-predominantly-truncating-gene rule is not used.
Not Applicable for this VCEP
The ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2 marks BP3 as not applicable. NM_000527.5:c.1775G>A in LDLR is a missense substitution predicted to produce NP_000518.1:p.(Gly592Glu). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The FH VCEP marks BP5 Not Applicable for this VCEP, so no alternate molecular basis evidence can be used to apply BP5.
Not Applicable for this VCEP
The FH VCEP marks BP6 Not Applicable for this VCEP; benign assertions from reputable sources cannot activate this criterion under the governing rule.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
NM_000527.5:c.1775G>A is a missense variant producing NP_000518.1:p.(Gly592Glu), not a synonymous variant. The VCEP BP7 rule is limited to synonymous variants and additionally requires BP4, so BP7 is outside its governing scope for this variant. The BP4 requirement is not reached because the variant fails the BP7 applicability requirement before evidence sufficiency is considered.
Variant is synonymous. Caveat: variant must also meet BP4 (i.e. no predicted impact on splicing).
Every interpreted variant in LDLR, mapped onto the exon structure of NM_000527.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)71 / 1,179,988 | 6e-052 hom |
| Admixed American2 / 59,954 | 3.3e-05 |
| Remaining individuals2 / 62,478 | 3.2e-05 |
| European (non-Finnish)15 / 129,176 | 0.00012 |
| Admixed American1 / 35,440 | 2.8e-05 |
This variant is present in gnomAD v4.1 (AF= 4.64709e-05; MAF= 0.00465%, 75/1613914 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 6.01701e-05; MAF= 0.00602%, 71/1179988 alleles, homozygotes = 2); grpmax FAF= 4.863e-05.
This variant is present in gnomAD v2.1 (AF= 5.65639e-05; MAF= 0.00566%, 16/282866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000116121; MAF= 0.01161%, 15/129176 alleles, homozygotes = 0); grpmax FAF= 0.00012682.
Absent from gnomAD-Canada v1.0.
NM_000527.5:c.1775G>A is a missense variant producing NP_000518.1:p.(Gly592Glu). The governing VCEP PP3 rule names REVEL >=0.75 for missense variants, or predicted splicing using MaxEntScan. The available REVEL score is 0.938, which meets the VCEP's missense threshold, so PP3 is met at Supporting strength. The available SpliceAI score was not used because SpliceAI is not the predictor named by this VCEP rule for the splicing pathway.
REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
NM_000527.5:c.1775G>A is a missense variant, so the VCEP BP4 missense pathway is in scope. The governing rule requires REVEL <=0.5 for the missense pathway, or no predicted impact to splicing using MaxEntScan. The available REVEL score is 0.938 and therefore does not meet the BP4 REVEL threshold. No MaxEntScan result is available, and the available SpliceAI result cannot substitute because SpliceAI is not the predictor named by the VCEP rule. BP4 therefore cannot be assessed from the available governing-rule evidence.
REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
NM_000527.5:c.1775G>A is a missense variant producing NP_000518.1:p.(Gly592Glu), not a synonymous variant. The VCEP BP7 rule is limited to synonymous variants and additionally requires BP4, so BP7 is outside its governing scope for this variant. The BP4 requirement is not reached because the variant fails the BP7 applicability requirement before evidence sufficiency is considered.
Variant is synonymous. Caveat: variant must also meet BP4 (i.e. no predicted impact on splicing).
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.938. BayesDel score = 0.591536.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
The 1775G>A mutation was responsible for all the homozygous patients in our area, indicating a founder effect.
Introduction; Table 1; Results, paragraph 1; Table 2; Discussion, paragraph 1
G571E GGG-tGAG 2A French <2
Table 2, section C: Epidermal Growth Factor Homology Domain (exons 7–14), exon 12
The study population was then divided into 2 groups according to the class of the LDLR mutation [patients sharing a class V mutation (the G1775A mutation, n = 21) and patients sharing class II mutations (the G1646A and the C858A mutations, n = 28)].
Abstract; Materials and Methods; Results, Table 4; Discussion
DNA analysis of FH patients is divided into several consecutive steps: 1) PCR-RFLP detection of the most common mutation in the APOB gene (p.Arg3527Gln) [28,29]; 2) PCR-RFLP detection of the most common mutations in the LDLR gene (p.Gly592Glu, p.Asp266Glu, and p.Arg416Trp);
Methods, Patients; Results, paragraph 1
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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= 4.64709e-05; MAF= 0.00465%, 75/1613914 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 6.01701e-05; MAF= 0.00602%, 71/1179988 alleles, homozygotes = 2); grpmax FAF= 4.863e-05.
This variant is present in gnomAD v2.1 (AF= 5.65639e-05; MAF= 0.00566%, 16/282866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000116121; MAF= 0.01161%, 15/129176 alleles, homozygotes = 0); grpmax FAF= 0.00012682.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (33 clinical laboratories) and as Likely pathogenic (4 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel (expert panel). (ClinVarID = 161271)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.938. BayesDel score = 0.591536.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52945923, n = 1 times).
This variant does not lie in a statistically significant hotspot.