rs45508991

Variant names:

• chr19-11123210-C-T
• rs45508991
• NM_000527.5:c.2177C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:BA1 - FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is Met.BP4 - REVEL = 0.454, it is below 0.50, so splicing evaluation is required.Functional data on splicing not available.A) variant not on limitsB) does not create AGC) variant is exonic and there 1 an AG nearby MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9--- BP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023649/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0073 (43 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Benign reviewed by expert panel B:29 O:1
• Conservation: PhyloP100: 0.0910
• Publications: 38 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.2177C>T	p.Thr726Ile	missense	Exon 15 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2177C>T	p.Thr726Ile	missense	Exon 15 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2054C>T	p.Thr685Ile	missense	Exon 14 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2177C>T	p.Thr726Ile	missense	Exon 15 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2435C>T	p.Thr812Ile	missense	Exon 15 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2177C>T	p.Thr726Ile	missense	Exon 15 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152138 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00998

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00789

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00548 AC: 1378 AN: 251244 AF XY: 0.00530

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.00859

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00730 AC: 10674 AN: 1461774 Hom.: 43 Cov.: 31 AF XY: 0.00715 AC XY: 5200 AN XY: 727170

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00233 AC: 104 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00321 AC: 84 AN: 26136

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

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.0122 AC: 652 AN: 53354

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00847 AC: 9417 AN: 1111958

Other (OTH) AF: 0.00613 AC: 370 AN: 60396

GnomAD4 genome AF: 0.00495 AC: 753 AN: 152256 Hom.: 4 Cov.: 30 AF XY: 0.00497 AC XY: 370 AN XY: 74458

African (AFR) AF: 0.000987 AC: 41 AN: 41556

American (AMR) AF: 0.00275 AC: 42 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00998 AC: 106 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00789 AC: 537 AN: 68020

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00634 Hom.: 8

Bravo AF: 0.00419

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00624 AC: 758

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00671

EpiControl AF: 0.00824

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	15	Hypercholesterolemia, familial, 1 (15)
-	-	6	not specified (6)
-	-	4	Familial hypercholesterolemia (4)
-	-	3	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	6.0
DANN	Benign	0.96
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.091
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.45
Sift	Benign	0.068	T
Sift4G	Uncertain	0.031	D
Polyphen		0.021	B
Vest4		0.25
MVP		0.99
MPC		0.23
ClinPred		0.016	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.67
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45508991; hg19: chr19-11233886; COSMIC: COSV99369873; COSMIC: COSV99369873;