rs199540175

Positions:

• chr19-11105625-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.694+25C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4: The variant is not predicted to affect the splicing process by SpliceAI. So, BP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA044382/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:6
• Conservation: PhyloP100: -1.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got -1 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.694+25C>T		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.694+25C>T		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 151906 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.000806 AC: 184 AN: 228260 Hom.: 0 AF XY: 0.000776 AC XY: 97 AN XY: 124984

Gnomad AFR exome AF: 0.00171

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000776

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.000440 AC: 623 AN: 1416870 Hom.: 1 Cov.: 31 AF XY: 0.000435 AC XY: 304 AN XY: 699322

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.0000403

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000348

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152024 Hom.: 1 Cov.: 33 AF XY: 0.00108 AC XY: 80 AN XY: 74320

Gnomad4 AFR AF: 0.00162

Gnomad4 AMR AF: 0.00361

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.000769 Hom.: 0

Bravo AF: 0.00137

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.694+25C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4: The variant is not predicted to affect the splicing process by SpliceAI. So, BP4 is met. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial hypercholesterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 09, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.82
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs199540175; hg19: chr19-11216301;