chr19-11123324-T-C

Variant names:

• chr19-11123324-T-C
• rs759440817
• NM_000527.5:c.2291T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. BS3 PM2 PP4 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2291T>C (p.Ile764Thr) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BP4 and BS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.0001337 (0.01337%) in East Asian exomes + genomes (gnomAD v4.1.0).PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon Broome criteria for possible FH from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded.BP4: REVEL = 0.352, it is below 0.50, so splicing evaluation required. Functional data on splicing not available. A) Variant not on limits.B) Does not create GT.C) There is a GT nearby. MES scores: variant cryptic = -5.73, wt cryptic = -8.16, canonical donor site = 9.06. Cryptic scores are negative, splice site not used. Variant is not predicted to alter splicing. BS3: Level 1 assay: PMID 34167030 (Alves et al., 2021): Heterologous cells (CHO), FACS; Result - > Normal cell surface LDLR (105%), LDL-LDLR binding (90%) and uptake (89%). Functional study is consistent with no damaging effect.Level 3 assay: PMID 37719435 (Graça et al., 2023): Heterologous cells (CHO), microscopy assays; Result - >100% LDLR expression and >100% LDLR activity. Functional study is consistent with no damaging effect.With the application of BP4 and BS3 and the functional evidence available, consensus was to classify this variant as Likely Benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA039387/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:4
• Conservation: PhyloP100: -1.72
• Publications: 2 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: Likely_benign. The variant received -2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2291T>C	p.Ile764Thr	missense	Exon 15 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2291T>C	p.Ile764Thr	missense	Exon 15 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.2168T>C	p.Ile723Thr	missense	Exon 14 of 17	NP_001182728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2291T>C	p.Ile764Thr	missense	Exon 15 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2549T>C	p.Ile850Thr	missense	Exon 15 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2291T>C	p.Ile764Thr	missense	Exon 15 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251168 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461830 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	Hypercholesterolemia, familial, 1 (4)
-	2	-	Familial hypercholesterolemia (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.0050
DANN	Benign	0.25
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.11	N
PhyloP100		-1.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.46	N
REVEL	Uncertain	0.35
Sift	Benign	0.86	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.016
MutPred		0.50		Gain of disorder (P = 0.0095)
MVP		0.82
MPC		0.27
ClinPred		0.021	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.71
Mutation Taster		=65/35	polymorphism

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: rs759440817; hg19: chr19-11234000;