chr19-11111541-C-A

Variant names:

• chr19-11111541-C-A
• rs200533979
• NM_000527.5:c.1088C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP4 BS3_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BS3_Supporting and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0).BP4: REVEL=0.345, it is below 0.50, splicing evaluation required. Functional data on splicing is not available. A) not on limits, B) does not create AG, C) there are two AG nearby:First AG -- MES score: variant cryptic site= 1.75, wt cryptic site= 2.69, canonical WT site=13.90. Ratio Var cryptic/Wt cryptic= 1.75/2.69=0.65 --- not above 1.1. Ratio Var cryptic/Wt canonical=1.75/13.90=0.92 --- it is above 0.9. Second AG -- MES score: variant cryptic site= -5.84, wt cryptic site= -3.45, canonical WT site=13.90.Variant not predicted to alter splicing.BS3_Supporting: Level 3 assay, PMID 37719435 (Graça et al., 2023): Heterologous cells (CHO), microscopy assays. Result: 90-100% LDLR expression and 95-98% LDLR activity. Functional study is consistent with no damaging effect.PP4: Variant meets PM2 and is identified in 1 case with Possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585297/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 0.733
• Publications: 4 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: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1088C>A	p.Thr363Asn	missense	Exon 8 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1088C>A	p.Thr363Asn	missense	Exon 8 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.965C>A	p.Thr322Asn	missense	Exon 7 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1088C>A	p.Thr363Asn	missense	Exon 8 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1346C>A	p.Thr449Asn	missense	Exon 8 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1088C>A	p.Thr363Asn	missense	Exon 8 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461516 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000170 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	Hypercholesterolemia, familial, 1 (4)
-	1	-	Familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.95	L
PhyloP100		0.73
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.019	D
Sift4G	Benign	0.069	T
Polyphen		0.49	P
Vest4		0.28
MutPred		0.41		Loss of phosphorylation at T363 (P = 0.0377)
MVP		1.0
MPC		0.81
ClinPred		0.93	D
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.91
Mutation Taster		=45/55	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200533979; hg19: chr19-11222217;