NM_000527.5:c.2389G>A

Variant names:

• chr19-11128085-G-A
• rs750518671
• NM_000527.5:c.2389G>A
• LDLR p.Val797Met

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM5PP3_ModeratePP5_Strong

The NM_000527.5(LDLR):c.2389G>A (p.Val797Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000434 (AC=7) in the gnomAD database across 1,613,688 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000207. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005427660: "In vitro functional studies have shown that this variant causes a reduction in LDLR internalization and expression at the cellular membrane (PMID:34497632)."" 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.V797L: Pathogenic/Likely_pathogenic (ClinVar VariationId 252298, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V797= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 891738); p.V797= (synonymous): Likely_benign (ClinVar VariationId 1094170, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LDLR NM_000527.5 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 U:3
• Conservation: PhyloP100: 2.41
• Publications: 32 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

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: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV005427660: "In vitro functional studies have shown that this variant causes a reduction in LDLR internalization and expression at the cellular membrane (PMID: 34497632)."; SCV006101202: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000589577: Functional splice studies of a different variant at this same nucleotide position (c.2389 G>T, p.V797L) demonstrate skipping of exon 16, further supporting the functional importance of this nucleotide position (PMID: 28169869);; SCV002047264: In addition, this variant is located at an exon-intron junction and an RT-PCR study suggests the variant may affect LDLR mRNA splicing (PMID: 9763532 (1998)).; SCV000904109: "In vitro functional studies have shown that this variant causes a reduction in LDLR internalization and expression at the cellular membrane (PMID: 34497632)."; SCV000731742: This variant has been shown to cause altered splicing leading to absent protein (Mak 1998).
	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: 6 pathogenic, 3 benign (OR vs. background: 9.3).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.V797L: Pathogenic/Likely_pathogenic (ClinVar VariationId 252298, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.V797= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 891738); p.V797= (synonymous): Likely_benign (ClinVar VariationId 1094170, 1 star)
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (23/26 total P/LP).

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.2389G>A p.Val797Met	missensesplice_region	Exon 16 of 18	Prot: NP_000518.1 UniProt:
	LDLR NM_001195798.2		c.2389G>A p.Val797Met	missensesplice_region	Exon 16 of 18	Prot: NP_001182727.1 UniProt:
	LDLR NM_001195799.2		c.2266G>A p.Val756Met	missensesplice_region	Exon 15 of 17	Prot: NP_001182728.1 UniProt:

LDLR NM_000527.5

MANE Select

HGVSc / HGVSpc.2389G>Ap.Val797Met

Exon rankExon 16 of 18

missensesplice_region

Prot: NP_000518.1UniProt: P01130-1

LDLR NM_001195798.2

HGVSc / HGVSpc.2389G>Ap.Val797Met

Exon rankExon 16 of 18

missensesplice_region

Prot: NP_001182727.1UniProt: P01130-5

LDLR NM_001195799.2

HGVSc / HGVSpc.2266G>Ap.Val756Met

Exon rankExon 15 of 17

missensesplice_region

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.2389G>A p.Val797Met	missensesplice_region	Exon 16 of 18	Prot: ENSP00000454071.1 UniProt:
	LDLR ENST00000252444.10	TSL:1	c.2647G>A p.Val883Met	missensesplice_region	Exon 16 of 18	Prot: ENSP00000252444.6 UniProt:
	LDLR ENST00000558013.5	TSL:1	c.2389G>A p.Val797Met	missensesplice_region	Exon 16 of 18	Prot: ENSP00000453346.1 UniProt:

LDLR ENST00000558518.6

TSL:1MANE Select

HGVSc / HGVSpc.2389G>Ap.Val797Met

Exon rankExon 16 of 18

missensesplice_region

Prot: ENSP00000454071.1UniProt: P01130-1

LDLR ENST00000252444.10

TSL:1

HGVSc / HGVSpc.2647G>Ap.Val883Met

Exon rankExon 16 of 18

missensesplice_region

Prot: ENSP00000252444.6UniProt: J3KMZ9

LDLR ENST00000558013.5

TSL:1

HGVSc / HGVSpc.2389G>Ap.Val797Met

Exon rankExon 16 of 18

missensesplice_region

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:152078	Cov:31
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251360	Cov:
GnomAD4 exome	AF: 0.00000342	AC:5	Hom:0	AN:1461610	Cov:32
GnomAD4 genome	AF: 0.0000132	AC:2	Hom:0	AN:152078	Cov:31
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:54058	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000195	2	102690	0.0000273	5	183358

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
12	3	-	Hypercholesterolemia, familial, 1 (15)
5	-	-	Familial hypercholesterolemia (5)
3	-	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dyslipidemia (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Benign	0.010
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Benign	0.17
GPN-Star LLR	N/A	-5.0
GPN-Star score	N/A	4.7
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.38	T
Mutation Taster	N/A	5/95	disease causing (ClinVar)
PhyloP100	Benign	2.4
popEVE	Benign	-3.0
PROVEAN	Benign	0.24	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.8
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.014	D
Varity_R	N/A	0.088
VESM-3B	Benign	-5.8

Showing 25 of 25 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
DS_DL_spliceai	Uncertain	0.32	Position offset: 0
Pangolin (max)	Uncertain	0.31
Pangolin loss	Uncertain	0.31	Position offset: 0
SpliceAI score (max)	Uncertain	0.32	Details are displayed if max score is > 0.2

Showing 6 of 6 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.

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: 1.06 · p.Val797Met (assay numbering)

No calibration data

This score is at approximately the 87th 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: 1.06 · p.Val797Met (assay numbering)

No calibration data

This score is at approximately the 86th 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: rs750518671;

hg19: chr19-11238761;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar