19-11116268-C-T

Variant names:

• chr19-11116268-C-T
• rs4508523
• NM_000527.5:c.1705+56C>T

Variant summary

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

The NM_000527.5(LDLR):​c.1705+56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,149,754 control chromosomes in the GnomAD database, including 18,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4568 hom., cov: 33)
  • Exomes 𝑓: 0.15 (14190 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.15
• Publications: 15 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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=-0.86).
• BP6: Variant 19-11116268-C-T is Benign according to our data. Variant chr19-11116268-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 251983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1705+56C>T		intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.1705+56C>T		intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.1582+56C>T		intron	N/A	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1705+56C>T		intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1963+56C>T		intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1705+56C>T		intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32698 AN: 152050 Hom.: 4552 Cov.: 33

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.153 AC: 152900 AN: 997586 Hom.: 14190 AF XY: 0.154 AC XY: 79333 AN XY: 515594

African (AFR) AF: 0.397 AC: 9567 AN: 24112

American (AMR) AF: 0.160 AC: 6967 AN: 43634

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3527 AN: 23132

East Asian (EAS) AF: 0.404 AC: 15061 AN: 37286

South Asian (SAS) AF: 0.176 AC: 13507 AN: 76758

European-Finnish (FIN) AF: 0.136 AC: 7140 AN: 52522

Middle Eastern (MID) AF: 0.129 AC: 631 AN: 4884

European-Non Finnish (NFE) AF: 0.129 AC: 89254 AN: 690184

Other (OTH) AF: 0.161 AC: 7246 AN: 45074

GnomAD4 genome AF: 0.215 AC: 32752 AN: 152168 Hom.: 4568 Cov.: 33 AF XY: 0.213 AC XY: 15851 AN XY: 74416

African (AFR) AF: 0.384 AC: 15929 AN: 41516

American (AMR) AF: 0.152 AC: 2321 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 541 AN: 3470

East Asian (EAS) AF: 0.375 AC: 1931 AN: 5150

South Asian (SAS) AF: 0.183 AC: 885 AN: 4826

European-Finnish (FIN) AF: 0.130 AC: 1378 AN: 10600

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9172 AN: 68016

Other (OTH) AF: 0.182 AC: 385 AN: 2110

Alfa AF: 0.161 Hom.: 9890

Bravo AF: 0.225

Asia WGS AF: 0.226 AC: 790 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.68
DANN	Benign	0.49
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4508523; hg19: chr19-11226944; COSMIC: COSV52944171; COSMIC: COSV52944171;