19-11113298-TTC-CTA

Variant names:

• chr19-11113298-TTC-CTA
• NM_000527.5:c.1207_1209delTTCinsCTA
• LDLR p.Phe403Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PS1PM1PM2

The NM_000527.5(LDLR):c.1207_1209delTTCinsCTA (p.Phe403Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.F403= (synonymous): Likely_benign (ClinVar VariationId 1557053, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18
• Publications: 0 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 ACMG Germline Pathogenicity v2019

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: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, 1-star ClinVar pathogenic — strong (PS1); ClinVar contains 2 P/LP entries with the same amino acid change (highest review level: 1 star).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 24 pathogenic, 0 benign (OR vs. background: 245.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

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.1207_1209delTTCinsCTA p.Phe403Leu	missense	N/A	Prot: NP_000518.1 UniProt:
	LDLR NM_001195798.2		c.1207_1209delTTCinsCTA p.Phe403Leu	missense	N/A	Prot: NP_001182727.1 UniProt:
	LDLR NM_001195799.2		c.1084_1086delTTCinsCTA p.Phe362Leu	missense	N/A	Prot: NP_001182728.1 UniProt:

LDLR NM_000527.5

MANE Select

HGVSc / HGVSpc.1207_1209delTTCinsCTAp.Phe403Leu

Exon rankN/A

missense

Prot: NP_000518.1UniProt: P01130-1

LDLR NM_001195798.2

HGVSc / HGVSpc.1207_1209delTTCinsCTAp.Phe403Leu

Exon rankN/A

missense

Prot: NP_001182727.1UniProt: P01130-5

LDLR NM_001195799.2

HGVSc / HGVSpc.1084_1086delTTCinsCTAp.Phe362Leu

Exon rankN/A

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.1207_1209delTTCinsCTA p.Phe403Leu	missense	N/A	Prot: ENSP00000454071.1 UniProt:
	LDLR ENST00000252444.10	TSL:1	c.1465_1467delTTCinsCTA p.Phe489Leu	missense	N/A	Prot: ENSP00000252444.6 UniProt:
	LDLR ENST00000558013.5	TSL:1	c.1207_1209delTTCinsCTA p.Phe403Leu	missense	N/A	Prot: ENSP00000453346.1 UniProt:

LDLR ENST00000558518.6

TSL:1MANE Select

HGVSc / HGVSpc.1207_1209delTTCinsCTAp.Phe403Leu

Exon rankN/A

missense

Prot: ENSP00000454071.1UniProt: P01130-1

LDLR ENST00000252444.10

TSL:1

HGVSc / HGVSpc.1465_1467delTTCinsCTAp.Phe489Leu

Exon rankN/A

missense

Prot: ENSP00000252444.6UniProt: J3KMZ9

LDLR ENST00000558013.5

TSL:1

HGVSc / HGVSpc.1207_1209delTTCinsCTAp.Phe403Leu

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:29
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:29

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	6.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

2 no calibration

2 assays found for this variant.

No calibration: 2 assays (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: 0.970 · p.Phe403Leu (assay numbering)

No calibration data

This score is at approximately the 63th 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.

Protein level

LDLR missense variant effects on LDLR cell-surface abundance.

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: 1.03 · p.Phe403Leu (assay numbering)

No calibration data

This score is at approximately the 77th 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

hg19: chr19-11223974;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar