The LDLR NM_000527.5:c.691T>G (NP_000518.1:p.(Cys231Gly)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
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: the missense variant is in LDLR exon 4 and its gnomAD v4.1 frequency is 1.93e-06, below the 0.0002 PM2 requirement.
Met at Moderate: the highest observed gnomAD population frequency is 5.741e-05 (0.00574%), below the VCEP PopMax MAF threshold of 0.0002 (0.02%).
Met: REVEL score 0.85 meets the VCEP PP3 missense threshold of ≥0.75 for Supporting evidence.
No benign criterion marked as applied in the recorded assessment.
VUS: PM1 (moderate), PM2 (moderate), and PP3 (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: 3 / 1,553,738 alleles. Recorded AF 1.93083e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 4.05696e-06; MAF= 0.00041%, 1/246490 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.54262e-05; MAF= 0.00554%, 1/18042 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.850. Refer to the recorded PP3/BP4 rationale for interpretation.
7 Pathogenic · 2 Likely pathogenic · 1 pathogenic. 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 ClinGen LDLR VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 4 not met · 12 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Among the requested codon, residue, domain, and missense-mechanism criteria, PM1 is met at Moderate strength because the variant is a missense change in exon 4 and satisfies the VCEP's PM2 frequency caveat.
PS1 is not met because no distinct pathogenic nucleotide change producing the same Cys231Gly amino-acid change was documented.
PM5 is not assessed because the available same-codon p.Cys231Arg report lacks the required pathogenic classification under these guidelines; PP2 and BP1 are not applicable under the LDLR VCEP.
The VCEP functional criteria cannot be assigned a pathogenic strength from the available audit trail because the reported damaging assay lacks an accessible primary report and sufficient endpoint/control details.
BS3 is not supported because no qualifying benign whole-cycle, RNA, minigene, or validated whole-cycle high-throughput result is available, and the reported 30–40% activity is incompatible with the VCEP benign thresholds.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
The exact variant is also reported as mature-protein C210G in several papers; the mature-protein numbering correspondence to precursor p.Cys231Gly was used only where the paper's nucleotide and amino-acid notation supported the match.
PS4 and PP4 remain not_assessed because the VCEP-specific case-count and validated-diagnosis requirements are not fully documented, despite PM2 being satisfied.
PP5, BP5, and BP6 are not_applicable under the VCEP.
Only PP3, BP4, and BP7 were adjudicated under the ClinGen Familial Hypercholesterolemia Expert Panel Version 1.2 specifications.
PP3 is met at Supporting strength from the VCEP-named REVEL missense path; BP4 is not assessed because its REVEL path fails and the required MaxEntScan result is unavailable; BP7 is not applicable because the variant is missense.
PM2 is met at Moderate strength because the highest observed gnomAD population frequency is 5.7411873e-05, below the VCEP threshold of 0.0002; BA1 and BS1 require unavailable PopMax FAF, and BS2 requires phenotype-qualified adult observations not supplied by gnomAD.
No criteria match.
The variant is a missense change in exon 4 of LDLR: NM_000527.5:c.691T>G, p.(Cys231Gly). The LDLR VCEP specifically defines PM1 Moderate for a missense variant located in exon 4 or for a missense change at one of 60 highly conserved cysteine residues, provided the variant also meets PM2. The variant is in exon 4, and gnomAD v4.1 reports total allele frequency 1.9308274625451653e-06 (3/1,553,738 alleles), with highest reported subpopulation AF 2.3936042893388866e-05, below the VCEP PM2 threshold of 0.0002. Therefore PM1 is met at Moderate strength.
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.
The governing VCEP assigns PM2 at Moderate strength when the variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD, with consideration of known founder exceptions. The highest observed population frequency available is 5.7411873e-05 (0.00574%) in the gnomAD v2.1 non-cancer East Asian subgroup, below the 0.0002 threshold; gnomAD v4.1 also remains below the threshold at 2.3936043e-05 (0.00239%). No evidence in the available materials establishes this variant as a known founder variant for purposes of the VCEP exception.
Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.
The VCEP specifies PP3 at Supporting strength for a missense variant with REVEL score ≥0.75, or for predicted splicing impact using MaxEntScan. NM_000527.5:c.691T>G is a missense variant, p.(Cys231Gly), and its REVEL score is 0.85, meeting the named missense threshold. The REVEL result is sufficient on the missense path; the separate splice-prediction path is not additionally counted.
REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
The queried missense variant is NM_000527.5:c.691T>G, NP_000518.1:p.(Cys231Gly). The available reports identify this same c.691T>G/C210G variant as pathogenic or disease-causing, but they do not establish a distinct pathogenic missense variant at codon 231 that produces the same Cys-to-Gly amino-acid change through a different nucleotide change. The VCEP rule therefore is not satisfied. SpliceAI predicts no significant splice impact for the queried variant (maximum delta score 0.016), but no qualifying same-amino-acid comparator is documented.
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 the candidate LDLR variant to be observed in an individual with a homozygous FH phenotype and exactly one other pathogenic or likely pathogenic variant in LDLR, APOB, or PCSK9 in trans, with PM2 also met. The exact c.691T>G/p.(Cys231Gly) variant is reported in a heterozygous FH proband with PCSK9 R46L, not in a documented homozygous-FH phenotype. A separate report describes a homozygous exon-4 nucleotide-691 variant inherited from both parents, but identifies it as c.691T>C/p.C210R rather than the queried c.691T>G/p.(Cys231Gly); therefore it is not qualifying evidence for this variant. The VCEP PM2 caveat is satisfied by gnomAD v4.1 total AF 1.93083e-06 and highest observed population AF 2.3936e-05, both below 0.0002, but the required homozygous-FH/in-trans observation is absent.
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.
No accessible study satisfies the VCEP's benign functional thresholds. The VCEP Strong BS3 path requires a heterologous-cell study of the whole LDLR cycle with >90% of wild-type activity in expression/biosynthesis, binding, and internalization; the Supporting paths require the specified >90% or >95% whole-cycle results, qualifying RNA or minigene results, or a validated whole-cycle high-throughput assay. The accessible exact-variant evidence instead reports near-normal expression with only 30–40% activity in two assays, although the primary report and assay endpoint are unavailable. PMID:10090473 reports 53% mutant transcript, which does not meet the VCEP benign RNA threshold of <10% aberrant transcript and does not establish benign protein function. Thus BS3 is not supported, and the available reported functional result is directionally incompatible with a benign functional interpretation.
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 VCEP requires an FH patient with a heterozygous phenotype to have a pathogenic or likely pathogenic variant in LDLR in trans, or in APOB or PCSK9, so that BP2 can be applied to an additional LDLR variant. The exact c.691T>G/p.(Cys231Gly) variant was reported in an FH heterozygote who also carried PCSK9 R46L, but the cited report does not classify R46L as pathogenic or likely pathogenic; its title and findings concern association with hypocholesterolemia. The evidence therefore does not establish the required qualifying pathogenic/likely pathogenic allelic partner. The same report also does not establish phase for the LDLR and PCSK9 variants, and no other qualifying partner is documented.
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.
The VCEP requires a de novo variant in a patient with the disease and no family history. The available variant-specific reports identify probands or familial cases but do not document confirmed de novo status, confirmed maternity and paternity, or absence of family history for NM_000527.5:c.691T>G (p.Cys231Gly). PMID:19073363 concerns a different reported protein change and describes inheritance from both parents, so it cannot establish PS2 for this variant.
Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences: https://clinicalgenome.org/working-groups/sequence-variant-interpretation/
The VCEP requires Level 1 for Strong PS3 or Level 2 for Moderate PS3. A ClinVar submission reports that published studies in transfected LDL-deficient CHO cells showed near-normal expression but only 30–40% activity in both 24- and 96-well assays, attributed to PMID 37719435. However, PMID 37719435 is not available in the case's source registry or paper extracts, and the available record does not establish which LDLR-cycle endpoint was measured, whether the assay followed the required Level 1 methodology, or whether appropriate validated controls were used. The accessible primary literature does not provide qualifying functional evidence for the exact p.Cys231Gly variant: PMID:10090473 reports normal-range mutant transcript quantity, while PMID:19073363 concerns an inconsistently reported different protein change (p.C210R). Therefore, the reported 30–40% result cannot be calibrated to a VCEP PS3 level from the available auditable evidence.
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. (2) RNA studies, using RNA extracted from heterozygous or true homozygous patient cells, where aberrant transcript is confirmed by sequencing and is quantified as >25% of total transcript from heterozygous cells or 50% of total transcript from homozygous cells. (3) Variants with two or more Level 3 functional studies (must be different assays); or any Level 3 functional study #1-4 performed by two or more independent labs with concordant results.
The VCEP permits PS4 at Supporting for 2-5 unrelated FH cases, Moderate for 6-9, or Strong for at least 10, and requires PM2. PM2 is satisfied: the highest observed gnomAD subpopulation AF is 0.0000554262 in v2.1 and 0.0000239360 in v4.1, each <=0.0002. The literature confirms the exact variant under mature-protein notation C210G: one proband in PMID:11313767, C210G listed among mutations in a cohort of 22 unrelated clinically diagnosed FH patients in PMID:10422804 without reporting how many of those 22 carried C210G, and one FH proband in PMID:16424354. PMID:19073363 reports a discrepant p.C210R annotation and cannot be counted as an exact p.Cys231Gly case. Because the available papers do not establish the number of unrelated exact-variant FH cases, no VCEP PS4 strength can be assigned.
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 VCEP PM5 Moderate rule requires a missense variant at the same codon as a variant classified pathogenic by these guidelines and predicting a different amino-acid change. PMID:19073363 describes a same-nucleotide c.691T>C/p.C210R report and also mentions c.691T>G, but the paper does not provide a VCEP/ACMG classification of the p.C210R comparator as pathogenic by these guidelines; it instead calls it a potential disease-causing mutation. The collected PM5 candidate search found no qualifying same-residue comparator. Thus the available evidence cannot establish the required pathogenic classification, and PM5 is not assessed.
Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.
The VCEP defines PM6 by reference to PS2. The available evidence does not establish an assumed de novo occurrence of the exact NM_000527.5:c.691T>G (p.Cys231Gly) variant: reports identify individual probands or familial cases, without documenting the necessary parental-origin evidence or a de novo interpretation for this variant.
See PS2 above.
The VCEP requires 2-3 informative meioses and at least one affected relative with LDL-C above the 75th centile for PP1 Supporting, 4-5 informative meioses and at least two such affected relatives for Moderate, or at least 6 informative meioses and at least two such affected relatives for Strong. The available reports do not provide a qualifying count of informative meioses or the required LDL-C percentile measurements for affected relatives carrying this exact variant. PMID:16424354 documents one proband carrying C210G, while the described mother carried PCSK9 R46L alone; this does not supply a qualifying segregating affected relative.
Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant. ... Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant. ... Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant.
The VCEP PP4 rule requires an LDLR variant in an FH patient whose diagnosis is based on validated clinical criteria such as DLCN >=6, Simon Broome possible/definite, or MEDPED, after alternative causes of high cholesterol are excluded, and also requires PM2. PM2 is met by the gnomAD data, but the available variant-specific records do not document a validated diagnostic score/category for the patient or exclusion of alternative causes. The papers identify the variant in FH cohorts or patients, but that documentation is insufficient to complete the VCEP PP4 rule.
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 a PopMax FAF of at least 0.005 in gnomAD. The available gnomAD v2.1 non-cancer exome and v4.1 all-comers records report observed population frequencies but do not provide PopMax FAF (the FAF fields are null), so the specified FAF threshold cannot be evaluated without substituting a different metric.
Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.
The governing VCEP requires a PopMax FAF of at least 0.002 in gnomAD. The available gnomAD v2.1 non-cancer exome and v4.1 all-comers records report observed population frequencies but do not provide PopMax FAF (the FAF fields are null), so the specified FAF threshold cannot be evaluated without substituting a different metric.
Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.
The governing VCEP requires the variant to be identified in at least three unrelated heterozygous or at least one homozygous well-phenotyped, untreated, normolipidemic adult. The available gnomAD records provide allele counts and homozygote counts but no individual-level lipid phenotype, treatment status, or unrelatedness, so this rule cannot be evaluated.
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, with at least two informative meioses in each family, and at least one unaffected relative with LDL-C below the 50th centile who carries the variant. The available evidence does not document two such families, the required meioses, or an unaffected carrier below that LDL-C threshold.
Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family. ... Caveat: must be ≥1 unaffected relative (LDL-C <50th centile) who is positive for the variant.
The VCEP specifies BP4 at Supporting strength for a missense variant with REVEL score ≤0.5, or with no predicted impact to splicing using MaxEntScan. The variant is missense and has REVEL 0.85, so the REVEL branch does not meet the BP4 threshold. A MaxEntScan result, which is the VCEP-named predictor for the alternative splice path, is not available. Other splice predictors are not substituted for MaxEntScan under this governing rule; therefore BP4 cannot be assessed.
REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
PVS1 is not applicable because the queried NM_000527.5:c.691T>G variant is a missense substitution, p.(Cys231Gly), in exon 4, with no canonical splice-consensus alteration; it is not a loss-of-function consequence for the VCEP PVS1 flow-diagram pathway. The VCEP provides only the instruction to use its PVS1 flow diagram and no evidence here supports a truncating, splice-disrupting, or other qualifying loss-of-function event.
See PVS1 flow diagram (Figure 1).
PM4 is not applicable because the variant is a missense substitution, p.(Cys231Gly), rather than an in-frame deletion or insertion smaller than one whole exon or an in-frame whole-exon duplication. The VCEP PM4 rule does not name missense substitutions as eligible variant types.
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 LDLR Familial Hypercholesterolemia VCEP explicitly marks PP2 as not applicable for this VCEP; no PP2 evidence is evaluated.
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 LDLR FH VCEP marks PP5 Not Applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The LDLR Familial Hypercholesterolemia VCEP explicitly marks BP1 as not applicable for this VCEP; no BP1 evidence is evaluated.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
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.691T>G in LDLR is a missense substitution predicted to produce NP_000518.1:p.(Cys231Gly). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The LDLR FH VCEP marks BP5 Not Applicable for this VCEP; therefore no alternate molecular basis evidence is evaluated under BP5.
Not Applicable for this VCEP
The LDLR FH VCEP marks BP6 Not Applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP BP7 rule applies only to synonymous variants and additionally requires BP4. NM_000527.5:c.691T>G is a missense variant producing p.(Cys231Gly), so it lies outside BP7's stated scope and BP7 is not applicable.
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 |
|---|
| East Asian1 / 41,778 | 2.4e-05 |
| South Asian1 / 89,914 | 1.1e-05 |
| European (non-Finnish)1 / 1,139,082 | 8.8e-07 |
| East Asian1 / 18,042 | 5.5e-05 |
This variant is present in gnomAD v4.1 (AF= 1.93083e-06; MAF= 0.00019%, 3/1553738 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.3936e-05; MAF= 0.00239%, 1/41778 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 4.05696e-06; MAF= 0.00041%, 1/246490 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.54262e-05; MAF= 0.00554%, 1/18042 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The VCEP specifies PP3 at Supporting strength for a missense variant with REVEL score ≥0.75, or for predicted splicing impact using MaxEntScan. NM_000527.5:c.691T>G is a missense variant, p.(Cys231Gly), and its REVEL score is 0.85, meeting the named missense threshold. The REVEL result is sufficient on the missense path; the separate splice-prediction path is not additionally counted.
REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
The VCEP specifies BP4 at Supporting strength for a missense variant with REVEL score ≤0.5, or with no predicted impact to splicing using MaxEntScan. The variant is missense and has REVEL 0.85, so the REVEL branch does not meet the BP4 threshold. A MaxEntScan result, which is the VCEP-named predictor for the alternative splice path, is not available. Other splice predictors are not substituted for MaxEntScan under this governing rule; therefore BP4 cannot be assessed.
REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
The VCEP BP7 rule applies only to synonymous variants and additionally requires BP4. NM_000527.5:c.691T>G is a missense variant producing p.(Cys231Gly), so it lies outside BP7's stated scope and BP7 is not applicable.
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 = 0.02). REVEL score = 0.85. BayesDel score = 0.575887.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
In contrast to the nonsense mutations and the 1705+1G→T mutation, the missense mutations D147Y, C210G, Q345R, and L380V had relative amounts of mutant transcripts within the normal range, ranging from 42% to 58%.
Table 1; Results, Allele-Specific Transcript Quantitation; Table 3
Preliminary data from extended analysis of the promoter and coding region in the LDLR gene in the study population revealed eight novel mutations, including five missense mutations (A29T, R60C, D203A, E237K, L364R), a promoter mutation at nucleotide position −59 (C→T), a splice site mutation IVS6-4G→A and a 2-bp deletion following nucleotide position 368 (occurring within a stretch of TC repeats in codons 101–103), in addition to several previously described mutations (R57C, D200G, E207K, C210G) in 22 unrelated FH patients ((25), authors’ unpublished data).
Results, paragraph 3
691T4G C210G 1A
Results, Table 1, Characterisation of LDLR and APOB mutations; LDLR exon 4
The patient heterozygous for R46L (proband in family L2864, Figure 3) was a female who was heterozygous for mutation C210G in the LDLR gene. At age 21, she had a value for total serum cholesterol of 12.5 mmol/L. At age 27, she had a 54% lower value for total serum cholesterol of 5.8 mmol/L on simvastatin 40 mg.
Results, Good Responders to Statin Therapy; Figure 3 and accompanying family-study paragraph
Proband 4 had a homozygous mutation in exon 4 at nucleotide 691, a T>C mutation, leading to a p.C210R substitution (Fig. 2E). ... The same nucleotide mutation 691T>G was detected in Norwegian, South African and English populations.
Results, ‘Identification of LDL-R mutations in Chinese FH patients,’ paragraph describing proband 4; Table 1, Family IV; Table 2, Proband 4; Table 3, p.C210R
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= 1.93083e-06; MAF= 0.00019%, 3/1553738 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.3936e-05; MAF= 0.00239%, 1/41778 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 4.05696e-06; MAF= 0.00041%, 1/246490 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.54262e-05; MAF= 0.00554%, 1/18042 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 251397)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.85. BayesDel score = 0.575887.
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.