LDLR p.Val436Ala

Variant names:

• chr19-11113398-T-C
• rs779732323
• NM_000527.5:c.1307T>C
• LDLR p.Val436Ala

Your query was ambiguous. Multiple possible variants found:

• chr19-11113398-T-C
• chr19-11113398-TG-CA
• chr19-11113398-TG-CC
• chr19-11113398-TG-CT

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO6_SupportingO7_SupportingO8_Supporting

The NM_000527.5(LDLR):c.1307T>C (p.Val436Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene LDLR is a known oncogene (CancerMine: 2 oncogene citations). The variant allele was found at a cumulative frequency of 0.00000806 (AC=13) in the gnomAD database across 1,613,722 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004087471: A functional study detected partial reduction of LDLR protein expression in cells derived from a patient heterozygous for this alteration" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.V436E: Likely_pathogenic (ClinVar VariationId 1518023, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V436M: Uncertain_significance (ClinVar VariationId 1172265, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1
• Conservation: PhyloP100: 6.06
• Publications: 3 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Natera
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000005 — very rare (O3 supporting [+1])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 33 pathogenic, 0 benign (OR vs. background: 335.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 0.61 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LDLR NM_000527.5	MANE Select	c.1307T>C p.Val436Ala	missense	Exon 9 of 18	Prot: NP_000518.1 UniProt:
	LDLR NM_001195798.2		c.1307T>C p.Val436Ala	missense	Exon 9 of 18	Prot: NP_001182727.1 UniProt:
	LDLR NM_001195799.2		c.1184T>C p.Val395Ala	missense	Exon 8 of 17	Prot: NP_001182728.1 UniProt:

LDLR NM_000527.5

MANE Select

HGVSc / HGVSpc.1307T>Cp.Val436Ala

Exon rankExon 9 of 18

missense

Prot: NP_000518.1UniProt: P01130-1

LDLR NM_001195798.2

HGVSc / HGVSpc.1307T>Cp.Val436Ala

Exon rankExon 9 of 18

missense

Prot: NP_001182727.1UniProt: P01130-5

LDLR NM_001195799.2

HGVSc / HGVSpc.1184T>Cp.Val395Ala

Exon rankExon 8 of 17

missense

Prot: NP_001182728.1UniProt: P01130-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LDLR ENST00000558518.6	TSL:1MANE Select	c.1307T>C p.Val436Ala	missense	Exon 9 of 18	Prot: ENSP00000454071.1 UniProt:
	LDLR ENST00000252444.10	TSL:1	c.1565T>C p.Val522Ala	missense	Exon 9 of 18	Prot: ENSP00000252444.6 UniProt:
	LDLR ENST00000558013.5	TSL:1	c.1307T>C p.Val436Ala	missense	Exon 9 of 18	Prot: ENSP00000453346.1 UniProt:

LDLR ENST00000558518.6

TSL:1MANE Select

HGVSc / HGVSpc.1307T>Cp.Val436Ala

Exon rankExon 9 of 18

missense

Prot: ENSP00000454071.1UniProt: P01130-1

LDLR ENST00000252444.10

TSL:1

HGVSc / HGVSpc.1565T>Cp.Val522Ala

Exon rankExon 9 of 18

missense

Prot: ENSP00000252444.6UniProt: J3KMZ9

LDLR ENST00000558013.5

TSL:1

HGVSc / HGVSpc.1307T>Cp.Val436Ala

Exon rankExon 9 of 18

missense

Prot: ENSP00000453346.1UniProt: P01130-5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000132	AC:2	Hom:0	AN:152042	Cov:29
GnomAD2 exomes	AF: 0.0000119	AC:3	Hom:	AN:251266	Cov:
GnomAD4 exome	AF: 0.00000753	AC:11	Hom:0	AN:1461680	Cov:33
GnomAD4 genome	AF: 0.0000132	AC:2	Hom:0	AN:152042	Cov:29
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000377	AC:2	Hom:0	AN:53064	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000144	1	69396	0.00000802	1	124680

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Familial hypercholesterolemia (6)
4	1	-	Hypercholesterolemia, familial, 1 (5)
5	-	-	not provided (5)
1	-	-	Cardiovascular phenotype (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.55
GPN-Star LLR	N/A	-6.9
GPN-Star score	N/A	6.9
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.59	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Benign	1.2	L
PhyloP100	Uncertain	6.1
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.6	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Varity_R	N/A	0.62
VESM-3B	Benign	-7.2

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 no calibration

1 assay found for this variant.

No calibration: 1 assay (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Protein level

LDLR missense variant effects on LDL uptake.

The functional landscape of coding variation in the familial hypercholesterolemia gene LDLR.

• Gene: LDLR
• Assay type: Flow cytometry assay
• Mechanism: Gain or loss of function
• Model system: Immortalized human cells
• Score: 0.926 · p.Val436Ala (assay numbering)

No calibration data

This score is at approximately the 51th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs779732323;

hg19: chr19-11224074;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar