rs5929

Variant names:

• chr19-11116124-C-T
• rs5929
• NM_000527.5:c.1617C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000527.5(LDLR):​c.1617C>T​(p.Pro539Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,612,458 control chromosomes in the GnomAD database, including 4,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (617 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3609 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -3.35
• 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-11116124-C-T is Benign according to our data. Variant chr19-11116124-C-T is described in ClinVar as Benign. ClinVar VariationId is 251936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

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.1617C>T	p.Pro539Pro	synonymous	Exon 11 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1617C>T	p.Pro539Pro	synonymous	Exon 11 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1494C>T	p.Pro498Pro	synonymous	Exon 10 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.1617C>T	p.Pro539Pro	synonymous	Exon 11 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1875C>T	p.Pro625Pro	synonymous	Exon 11 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1617C>T	p.Pro539Pro	synonymous	Exon 11 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11031 AN: 152010 Hom.: 614 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0565

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.0848

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0404

Gnomad OTH AF: 0.0755

GnomAD2 exomes AF: 0.0756 AC: 19015 AN: 251466 AF XY: 0.0735

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0760

Gnomad ASJ exome AF: 0.0667

Gnomad EAS exome AF: 0.271

Gnomad FIN exome AF: 0.0533

Gnomad NFE exome AF: 0.0425

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0532 AC: 77739 AN: 1460330 Hom.: 3609 Cov.: 30 AF XY: 0.0536 AC XY: 38940 AN XY: 726536

African (AFR) AF: 0.116 AC: 3881 AN: 33408

American (AMR) AF: 0.0738 AC: 3298 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 1657 AN: 26120

East Asian (EAS) AF: 0.298 AC: 11820 AN: 39668

South Asian (SAS) AF: 0.0801 AC: 6903 AN: 86202

European-Finnish (FIN) AF: 0.0541 AC: 2890 AN: 53374

Middle Eastern (MID) AF: 0.0550 AC: 317 AN: 5764

European-Non Finnish (NFE) AF: 0.0392 AC: 43506 AN: 1110736

Other (OTH) AF: 0.0575 AC: 3467 AN: 60340

GnomAD4 genome AF: 0.0726 AC: 11048 AN: 152128 Hom.: 617 Cov.: 32 AF XY: 0.0746 AC XY: 5546 AN XY: 74372

African (AFR) AF: 0.110 AC: 4580 AN: 41504

American (AMR) AF: 0.0566 AC: 864 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3468

East Asian (EAS) AF: 0.283 AC: 1460 AN: 5156

South Asian (SAS) AF: 0.0853 AC: 411 AN: 4820

European-Finnish (FIN) AF: 0.0524 AC: 556 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0404 AC: 2748 AN: 68002

Other (OTH) AF: 0.0771 AC: 163 AN: 2114

Alfa AF: 0.0573 Hom.: 330

Bravo AF: 0.0757

Asia WGS AF: 0.154 AC: 535 AN: 3478

EpiCase AF: 0.0436

EpiControl AF: 0.0404

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	Hypercholesterolemia, familial, 1 (8)
-	-	4	not specified (4)
-	-	3	Familial hypercholesterolemia (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Smith-Lemli-Opitz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.19
DANN	Benign	0.45
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=98/2	polymorphism (auto)

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: rs5929; hg19: chr19-11226800; COSMIC: COSV52943556; COSMIC: COSV52943556;