19-11116790-G-T

Variant names:

• chr19-11116790-G-T
• rs7259278
• NM_000527.5:c.1706-69G>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.1706-69G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,569,414 control chromosomes in the GnomAD database, including 23,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4311 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18979 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.85
• Publications: 6 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=-0.87).
• BP6: Variant 19-11116790-G-T is Benign according to our data. Variant chr19-11116790-G-T is described in ClinVar as Benign. ClinVar VariationId is 251985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 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.1706-69G>T		intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.1706-69G>T		intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.1583-69G>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.1706-69G>T		intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1964-69G>T		intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1706-69G>T		intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32053 AN: 152038 Hom.: 4298 Cov.: 33

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.180

GnomAD4 exome AF: 0.152 AC: 215490 AN: 1417258 Hom.: 18979 AF XY: 0.152 AC XY: 107736 AN XY: 707552

African (AFR) AF: 0.388 AC: 12626 AN: 32580

American (AMR) AF: 0.159 AC: 7114 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 3994 AN: 25878

East Asian (EAS) AF: 0.403 AC: 15893 AN: 39458

South Asian (SAS) AF: 0.176 AC: 15027 AN: 85330

European-Finnish (FIN) AF: 0.136 AC: 7125 AN: 52278

Middle Eastern (MID) AF: 0.146 AC: 605 AN: 4134

European-Non Finnish (NFE) AF: 0.134 AC: 143632 AN: 1074180

Other (OTH) AF: 0.161 AC: 9474 AN: 58764

GnomAD4 genome AF: 0.211 AC: 32100 AN: 152156 Hom.: 4311 Cov.: 33 AF XY: 0.209 AC XY: 15543 AN XY: 74386

African (AFR) AF: 0.369 AC: 15332 AN: 41506

American (AMR) AF: 0.151 AC: 2298 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 543 AN: 3470

East Asian (EAS) AF: 0.374 AC: 1931 AN: 5162

South Asian (SAS) AF: 0.180 AC: 869 AN: 4824

European-Finnish (FIN) AF: 0.130 AC: 1376 AN: 10598

Middle Eastern (MID) AF: 0.158 AC: 46 AN: 292

European-Non Finnish (NFE) AF: 0.135 AC: 9159 AN: 68012

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.150 Hom.: 932

Bravo AF: 0.220

Asia WGS AF: 0.223 AC: 777 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:3

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: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

3 hmz + 28 htz / 125 non-FH individuals

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	-0.87
CADD	Benign	0.18
DANN	Benign	0.66
PhyloP100		-1.9
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: rs7259278; hg19: chr19-11227466; COSMIC: COSV52946963; COSMIC: COSV52946963;