rs11669576

Variant names:

• chr19-11111624-G-A
• rs11669576
• NM_000527.5:c.1171G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11111624-G-A
• chr19-11111624-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BS2 BA1 BP4 BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.1752 (17.52%) in African exomes (gnomAD v2.1.1); frequency meets BA1 >0.5%BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in 1894 normolipidemic individuals, as well as in homozygosity in 58 normolipidemic individuals.BP2 - Case-level data present in VCI indicates this variant has been identified to co-occur with Pathogenic LDLR variants in at least 3 index cases with heterozygous FH phenotype.BP4 - REVEL = 0.309; score is below BP4 threshold of <0.50. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023426/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.080 (764 hom., cov: 31)
  • Exomes 𝑓: 0.048 (2184 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Benign reviewed by expert panel B:27 O:1
• Conservation: PhyloP100: -0.270
• Publications: 79 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 -14 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.1171G>A	p.Ala391Thr	missense	Exon 8 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1171G>A	p.Ala391Thr	missense	Exon 8 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1048G>A	p.Ala350Thr	missense	Exon 7 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.1171G>A	p.Ala391Thr	missense	Exon 8 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1429G>A	p.Ala477Thr	missense	Exon 8 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1171G>A	p.Ala391Thr	missense	Exon 8 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12192 AN: 152174 Hom.: 765 Cov.: 31

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0434 AC: 10892 AN: 250704 AF XY: 0.0408

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0487

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0475 AC: 69434 AN: 1461152 Hom.: 2184 Cov.: 32 AF XY: 0.0460 AC XY: 33454 AN XY: 726870

African (AFR) AF: 0.188 AC: 6296 AN: 33464

American (AMR) AF: 0.0287 AC: 1283 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 598 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.00527 AC: 455 AN: 86258

European-Finnish (FIN) AF: 0.0451 AC: 2390 AN: 52976

Middle Eastern (MID) AF: 0.0277 AC: 160 AN: 5768

European-Non Finnish (NFE) AF: 0.0496 AC: 55160 AN: 1111782

Other (OTH) AF: 0.0512 AC: 3090 AN: 60374

GnomAD4 genome AF: 0.0801 AC: 12198 AN: 152292 Hom.: 764 Cov.: 31 AF XY: 0.0761 AC XY: 5669 AN XY: 74454

African (AFR) AF: 0.179 AC: 7425 AN: 41550

American (AMR) AF: 0.0437 AC: 668 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4834

European-Finnish (FIN) AF: 0.0449 AC: 477 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0495 AC: 3370 AN: 68022

Other (OTH) AF: 0.0577 AC: 122 AN: 2116

Alfa AF: 0.0573 Hom.: 1018

Bravo AF: 0.0855

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.173 AC: 762

ESP6500EA AF: 0.0484 AC: 416

ExAC AF: 0.0464 AC: 5631

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0499

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	13	Hypercholesterolemia, familial, 1 (13)
-	-	7	not specified (7)
-	-	4	Familial hypercholesterolemia (4)
-	-	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	5.0
DANN	Benign	0.22
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-2.1	N
PhyloP100		-0.27
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.68	N
REVEL	Uncertain	0.31
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.019
MPC		0.24
ClinPred		0.0040	T
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.82
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11669576; hg19: chr19-11222300; COSMIC: COSV52943212; COSMIC: COSV52943212;