rs146354103

Variant names:

• chr19-11105413-C-T
• rs146354103
• NM_000527.5:c.507C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP7 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.507C>T (p.Asn169=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025.The supporting evidence is as follows:BP4: No REVEL, splicing evaluation required. Functional data on splicing not available. A) not on limits; B) does not create AG/GT; C) there is an AG nearby. MES scores: variant cryptic = -0.72, wt cryptic = -0.20, canonical acceptor = 8.16. Ratio variant cryptic/wt cryptic: -0.72/-0.20 = 3.6 --- it is above 1.1. Ratio variant cryptic/canonical acceptor: -0.72/8.16 = -0.09 --- it is not above 0.9. Variant is not predicted to alter splicing. PP3 is not met. BP4 is met.BP7: Variant is synonymous and meets BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023711/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:14
• Conservation: PhyloP100: -6.65
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.507C>T	p.Asn169Asn	synonymous	Exon 4 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.507C>T	p.Asn169Asn	synonymous	Exon 4 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.384C>T	p.Asn128Asn	synonymous	Exon 3 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.507C>T	p.Asn169Asn	synonymous	Exon 4 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.765C>T	p.Asn255Asn	synonymous	Exon 4 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.507C>T	p.Asn169Asn	synonymous	Exon 4 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000326 AC: 82 AN: 251282 AF XY: 0.000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00218

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000217 AC: 317 AN: 1461694 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 147 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00220 AC: 117 AN: 53264

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

European-Non Finnish (NFE) AF: 0.000164 AC: 182 AN: 1111980

Other (OTH) AF: 0.000199 AC: 12 AN: 60388

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74502

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000413 Hom.: 0

Bravo AF: 0.000125

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	5	Hypercholesterolemia, familial, 1 (8)
-	-	4	Familial hypercholesterolemia (4)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LDLR-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.22
DANN	Benign	0.76
PhyloP100		-6.7
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs146354103; hg19: chr19-11216089; COSMIC: COSV52944220; COSMIC: COSV52944220;