19-11120082-G-T

Variant names:

• chr19-11120082-G-T
• rs368243304
• NM_000527.5:c.1846-10G>T

Variant summary

Our verdict is Likely benign. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP2

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1846-10G>T variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (PM2, BP2 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - PopMax MAF = 0.00009643 (0.0096%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1).BP2 - Variant identified in an index case with heterozygous FH phenotype (LDLc = 6.5 mmol/l) and APOB variant p.(Arg3527Gln), classified as Pathogenic by the general ACMG guidelines from Robarts Research Institute.BP4 - No REVEL available, splicing evaluation needed. Functional data on splicing not available. A) variant is located at -20 to +3 bases of canonical acceptor splicing site MES scores: de novo acceptor = 11.36, authentic acceptor = 9.58. Ratio variant/wt = 1.18. It is above 1.0. B) The variant is located within range but does not create de novo GT site. C) Variant not on limits. Variant is not predicted to alter splicing. So BP4 is met.Variant has 2 BP evidence codes towards Benign, enough to classify as Likely benign, and only 1 PM evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA037094/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: LDLR NM_000527.5 intron
• Scores: Splicing: ADA: 0.00002065
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: -0.629
• Publications: 0 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

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

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.1846-10G>T		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1846-10G>T		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1723-10G>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.1846-10G>T		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2104-10G>T		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1846-10G>T		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 11 AN: 251482 AF XY: 0.0000589

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461676 Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26 AN XY: 727166

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111812

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74356

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.000197 AC: 3 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000215 Hom.: 0

Bravo AF: 0.000110

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	Hypercholesterolemia, familial, 1 (5)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.042
DANN	Benign	0.52
PhyloP100		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.010
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: rs368243304; hg19: chr19-11230758;