rs137853964 — LDLR Val827Ile / Val827Phe

LDLR Val827 — An Uncertain Signal in a Critical Gene

The [LDLR gene | low-density lipoprotein receptor gene; mutations cause familial hypercholesterolemia (FH), one of the most common serious inherited disorders, affecting ~1 in 250 people worldwide] is the master regulator of LDL cholesterol clearance from the bloodstream. The LDLR protein captures LDL particles circulating in blood and shuttles them into liver cells for degradation, keeping circulating LDL-C in check. When LDLR function is reduced or absent — as in classical FH — LDL-C accumulates and accelerates atherosclerosis.

rs137853964 sits in exon 18 of LDLR at chromosome 19 position 11,129,602 (GRCh38). This single nucleotide position carries two possible alternate alleles: G>A (producing Val827Ile) and G>T (producing Val827Phe). Both affect the same amino acid in the same functionally important domain, but they carry meaningfully different evidence profiles. The G>A change (Val827Ile) is the far more common variant; the G>T change (Val827Phe) is extremely rare.

The Mechanism

Position 827 of the LDLR protein lies within the [NPXY internalization motif | A short amino acid sequence (Asn-Pro-X-Tyr, where X is any amino acid) located in the cytoplasmic tail of LDLR at residues 823–828. This signal is recognized by clathrin adaptor proteins (AP-2), which concentrate LDL receptors into clathrin-coated pits for endocytosis. Disrupting NPXY prevents receptor internalization, trapping LDLR at the cell surface where it cannot deliver LDL for degradation] of the receptor's cytoplasmic tail. The NPXY sequence (amino acids 823–828) is the docking signal that allows the receptor, once it has captured an LDL particle at the cell surface, to be internalized into the cell via clathrin-coated pits.

Mutations in the NPXY motif classically impair receptor internalization — even if the LDL-binding domain remains intact, the receptor gets "stuck" at the cell surface and cannot recycle LDL into the cell. However, the position of Val827 within the NPXY sequence matters: the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel noted that position 827 "is variable" within the NPXY signal, meaning not every amino acid at this position is equally constrained.

Thormaehlen et al. 2015¹¹ Thormaehlen et al. 2015
Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction performed functional LDL uptake assays on 253 LDLR missense variants. Val827Ile (G>A) showed no significant effect on LDL uptake, placing it in the "functionally benign" category despite its location in the NPXY motif. The Val827Phe change (G>T) has not been studied in functional assays; its REVEL score of 0.86 suggests possible damaging effects, and it has been observed in two Moroccan individuals with clinical FH.

The Evidence

The two variants at rs137853964 have divergent evidence:

Val827Ile (G>A) — the common alternate: The ClinGen FH Variant Curation Expert Panel²² ClinGen FH Variant Curation Expert Panel
an expert panel applying ACMG/AMP criteria specifically calibrated for FH variants, using ClinGen's CSpec framework for LDLR classified Val827Ile as uncertain significance in June 2021, applying evidence codes PP1 (segregation with FH phenotype in 3 informative meioses) and PP3 (REVEL 0.771 exceeds the 0.75 threshold). Competing evidence from 7 submissions of Likely Benign or Benign classification reflects the functional assay null result and the striking Ashkenazi Jewish enrichment (~1.44% allele frequency — approximately 14-fold above the expected maximum frequency for a typical FH-causing variant). One homozygous individual has been identified in the Ashkenazi Jewish population without apparent severe FH, further undermining pathogenic classification.

Sun et al. 2018³³ Sun et al. 2018
Effects of Genetic Variants Associated with FH on LDL-C and Cardiovascular Outcomes in the Million Veteran Program demonstrated that LDLR variants with null functional assay results are indistinguishable from non-carriers in terms of LDL-C levels and cardiovascular event rates in population-scale data. This strongly argues that Val827Ile, with its confirmed null functional result, does not cause clinically meaningful LDL receptor impairment.

Val827Phe (G>T) — the rare alternate: The G>T change has five ClinVar submissions: two Likely Pathogenic (Invitae/Labcorp, Centre de Génétique Moléculaire) and three Uncertain Significance (ClinGen Expert Panel, Broad Institute, All of Us). It is [absent from gnomAD | not observed in ~800,000 population-control alleles], consistent with it being extremely rare. Alhababi et al. 2018⁴⁴ Alhababi et al. 2018
Spectrum of mutations of FH in Arab countries reported it in 2 Moroccan FH patients. Without functional assay data, pathogenicity cannot be confirmed, though the rarity and in silico predictions lean toward possible pathogenicity.

Practical Implications

For carriers of the common G>A change (Val827Ile): current evidence does not establish this as a disease-causing FH variant. The functional assay null result and high Ashkenazi Jewish frequency are strong arguments for clinical benignity, even though the ClinGen Expert Panel maintains an uncertain significance classification pending additional segregation and functional data. If your lipid panel shows elevated LDL-C, investigate other causes — lifestyle, diet, secondary causes (thyroid, medications), or other FH genes (APOB, PCSK9).

For carriers of the rare G>T change (Val827Phe): the evidence leans toward possible pathogenicity, but formal confirmation is lacking. Clinical lipid evaluation and cascade family screening are prudent steps while the scientific community accumulates more data.

In both cases, LDL-C measurement is more immediately actionable than genotype alone for determining whether lipid-lowering intervention is warranted.

Interactions

LDLR variants interact with other genes in the LDL clearance pathway. Carrying rs137853964 alongside variants in:

• PCSK9 (rs11591147 R46L) — PCSK9 loss-of-function variants lower LDL by reducing LDLR degradation. If Val827Ile proves benign, a PCSK9 R46L carrier will have an unchanged cardioprotective benefit.
• APOB (rs693, rs5742904) — APOB mutations reduce LDL-receptor binding affinity, compounding any LDL clearance deficit. If both APOB and LDLR are affected, LDL-C elevation would be expected to be more severe.
• APOE ε4 (rs429358) — APOE4 raises LDL and cardiovascular risk independently of LDLR, and compound FH+APOE4 genotypes are associated with particularly aggressive atherosclerosis.

If Val827Ile is eventually reclassified as benign, these interaction considerations become moot for this variant. If Val827Phe is confirmed pathogenic, compound heterozygosity with other LDLR variants would carry significantly elevated risk of severe FH.