rs147509697

Variant names:

• chr19-11089606-G-A
• rs147509697
• NM_000527.5:c.58G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11089606-G-A
• chr19-11089606-G-C
• chr19-11089606-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. BS3 BS4 PP1_Moderate BS2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) 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: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database.BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met.BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy.Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023728/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:6 B:18 O:1
• Conservation: PhyloP100: 1.04
• Publications: 19 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-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

ACMG classification

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

Our verdict: Benign. The variant received -10 ACMG points.

• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BS4: 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.58G>A	p.Gly20Arg	missense	Exon 1 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.58G>A	p.Gly20Arg	missense	Exon 1 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.58G>A	p.Gly20Arg	missense	Exon 1 of 17	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.58G>A	p.Gly20Arg	missense	Exon 1 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000558013.5	TSL:1	c.58G>A	p.Gly20Arg	missense	Exon 1 of 18	ENSP00000453346.1	P01130-5
	LDLR	ENST00000557933.5	TSL:5	c.58G>A	p.Gly20Arg	missense	Exon 1 of 18	ENSP00000453557.1	H0YMD1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000743 AC: 182 AN: 245116 AF XY: 0.000838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00243

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000917

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.000423 AC: 617 AN: 1459798 Hom.: 1 Cov.: 31 AF XY: 0.000442 AC XY: 321 AN XY: 726128

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.000538 AC: 24 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86082

European-Finnish (FIN) AF: 0.000965 AC: 51 AN: 52830

Middle Eastern (MID) AF: 0.000961 AC: 5 AN: 5204

European-Non Finnish (NFE) AF: 0.000401 AC: 446 AN: 1111612

Other (OTH) AF: 0.000548 AC: 33 AN: 60236

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74460

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.000982 AC: 15 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.000521

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000899 AC: 109

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	5	4	Hypercholesterolemia, familial, 1 (10)
-	-	5	not specified (5)
-	-	4	Familial hypercholesterolemia (4)
-	-	3	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypercholesterolemia (1)
-	-	1	LDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.97
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.56
Sift	Benign	0.19	T
Sift4G	Benign	0.56	T
Polyphen		0.12	B
Vest4		0.13
MutPred		0.56		Gain of MoRF binding (P = 0.0221)
MVP		1.0
MPC		0.35
ClinPred		0.025	T
GERP RS		0.32
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.12
gMVP		0.72
Mutation Taster		=83/17	polymorphism

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: rs147509697; hg19: chr19-11200282;