rs1799898

Variant names:

• chr19-11116878-C-T
• rs1799898
• NM_000527.5:c.1725C>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.1725C>T​(p.Leu575Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,613,742 control chromosomes in the GnomAD database, including 13,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (994 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12012 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.878
• Publications: 54 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=-0.55).
• BP6: Variant 19-11116878-C-T is Benign according to our data. Variant chr19-11116878-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 251997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.878 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 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.1725C>T	p.Leu575Leu	synonymous	Exon 12 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1725C>T	p.Leu575Leu	synonymous	Exon 12 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1602C>T	p.Leu534Leu	synonymous	Exon 11 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.1725C>T	p.Leu575Leu	synonymous	Exon 12 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1983C>T	p.Leu661Leu	synonymous	Exon 12 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1725C>T	p.Leu575Leu	synonymous	Exon 12 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16752 AN: 152056 Hom.: 991 Cov.: 32

Gnomad AFR AF: 0.0821

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.00752

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.112 AC: 28272 AN: 251468 AF XY: 0.117

Gnomad AFR exome AF: 0.0821

Gnomad AMR exome AF: 0.0702

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.00680

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.124 AC: 181747 AN: 1461568 Hom.: 12012 Cov.: 37 AF XY: 0.125 AC XY: 91118 AN XY: 727090

African (AFR) AF: 0.0811 AC: 2716 AN: 33476

American (AMR) AF: 0.0715 AC: 3197 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3663 AN: 26134

East Asian (EAS) AF: 0.00662 AC: 263 AN: 39700

South Asian (SAS) AF: 0.132 AC: 11352 AN: 86244

European-Finnish (FIN) AF: 0.130 AC: 6938 AN: 53414

Middle Eastern (MID) AF: 0.149 AC: 847 AN: 5676

European-Non Finnish (NFE) AF: 0.131 AC: 145417 AN: 1111824

Other (OTH) AF: 0.122 AC: 7354 AN: 60378

GnomAD4 genome AF: 0.110 AC: 16766 AN: 152174 Hom.: 994 Cov.: 32 AF XY: 0.110 AC XY: 8200 AN XY: 74384

African (AFR) AF: 0.0820 AC: 3407 AN: 41542

American (AMR) AF: 0.0864 AC: 1319 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3468

East Asian (EAS) AF: 0.00773 AC: 40 AN: 5174

South Asian (SAS) AF: 0.127 AC: 611 AN: 4828

European-Finnish (FIN) AF: 0.122 AC: 1291 AN: 10578

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 9009 AN: 68010

Other (OTH) AF: 0.129 AC: 273 AN: 2116

Alfa AF: 0.125 Hom.: 1485

Bravo AF: 0.105

Asia WGS AF: 0.0910 AC: 317 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.140

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Hypercholesterolemia, familial, 1 (7)
-	-	6	not specified (6)
-	-	4	Familial hypercholesterolemia (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.1
DANN	Benign	0.69
PhyloP100		-0.88
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1799898; hg19: chr19-11227554; COSMIC: COSV52943496; COSMIC: COSV52943496;