rs6511720

Variant names:

• chr19-11091630-G-T
• rs6511720
• NM_000527.5:c.67+2015G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000558518.6(LDLR):​c.67+2015G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,196 control chromosomes in the GnomAD database, including 1,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.11 (1095 hom., cov: 32)
• Consequence: LDLR ENST00000558518.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.224
• Publications: 317 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-11091630-G-T is Benign according to our data. Variant chr19-11091630-G-T is described in ClinVar as Benign. ClinVar VariationId is 250988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000558518.6. 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.67+2015G>T		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.67+2015G>T		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.67+2015G>T		intron	N/A	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.67+2015G>T		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.325+711G>T		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.67+2015G>T		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17315 AN: 152078 Hom.: 1098 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.0934

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.00769

Gnomad SAS AF: 0.0732

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.116

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.114 AC: 17318 AN: 152196 Hom.: 1095 Cov.: 32 AF XY: 0.114 AC XY: 8459 AN XY: 74416

African (AFR) AF: 0.135 AC: 5611 AN: 41514

American (AMR) AF: 0.0932 AC: 1424 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 461 AN: 3472

East Asian (EAS) AF: 0.00771 AC: 40 AN: 5188

South Asian (SAS) AF: 0.0720 AC: 347 AN: 4818

European-Finnish (FIN) AF: 0.115 AC: 1218 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7812 AN: 68004

Other (OTH) AF: 0.115 AC: 244 AN: 2116

Alfa AF: 0.113 Hom.: 4872

Bravo AF: 0.116

Asia WGS AF: 0.0570 AC: 200 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypercholesterolemia, familial, 1 (2)
-	-	1	Familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.71
PhyloP100		-0.22
Mutation Taster		=100/0	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: rs6511720; hg19: chr19-11202306;