rs55792959

Positions:

• chr19-11110613-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.941-39C>T variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and 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: BA1: FAF=0.005249 (0.5249%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So BA1 is met.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/CA030745/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (32 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign reviewed by expert panel U:3 B:9
• Conservation: PhyloP100: -0.0280

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 Benign. Variant got -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.941-39C>T		intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.941-39C>T		intron_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 623 AN: 152080 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00663

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00364 AC: 908 AN: 249520 Hom.: 5 AF XY: 0.00384 AC XY: 519 AN XY: 135180

Gnomad AFR exome AF: 0.000931

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00489

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00128

Gnomad FIN exome AF: 0.00318

Gnomad NFE exome AF: 0.00561

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00561 AC: 8191 AN: 1459876 Hom.: 32 Cov.: 31 AF XY: 0.00558 AC XY: 4049 AN XY: 726214

Gnomad4 AFR exome AF: 0.000927

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00490

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00162

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.00653

Gnomad4 OTH exome AF: 0.00561

GnomAD4 genome AF: 0.00409 AC: 623 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.00376 AC XY: 280 AN XY: 74406

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00413

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00663

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00493 Hom.: 0

Bravo AF: 0.00441

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:3 Benign:3

Benign, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.941-39C>T variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and 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: BA1: FAF=0.005249 (0.5249%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So BA1 is met. BP4: The variant is not predicted to affect the splicing process by SpliceAI. So, BP4 is met. -
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, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2018	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	LDLR: BS2 -

Familial hypercholesterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 06, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.5
DANN	Benign	0.66
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: rs55792959; hg19: chr19-11221289;