19-11120113-A-G

Variant names:

• chr19-11120113-A-G
• rs555292896
• NM_000527.5:c.1867A>G

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. BS1 PP1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1867A>G (p.Ile623Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1 and PP1 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: The supporting evidence is as follows: BS1: PopMax FAF= 0.002650 (0.265%) in East Asian exomes (gnomAD v2.1.1). PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 family from Laboratory of Genetics and Molecular Cardiology, Brazil. LINK:https://erepo.genome.network/evrepo/ui/classification/CA037254/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3 B:8
• Conservation: PhyloP100: 0.108
• Publications: 7 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

Our verdict: Uncertain_significance. The variant received -3 ACMG points.

• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.1867A>G	p.Ile623Val	missense	Exon 13 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1867A>G	p.Ile623Val	missense	Exon 13 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1744A>G	p.Ile582Val	missense	Exon 12 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.1867A>G	p.Ile623Val	missense	Exon 13 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2125A>G	p.Ile709Val	missense	Exon 13 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1867A>G	p.Ile623Val	missense	Exon 13 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 251494 AF XY: 0.000280

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461860 Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38 AN XY: 727230

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.000447 AC: 27 AN: 60394

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000656 Hom.: 0

Bravo AF: 0.000189

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	2	2	Hypercholesterolemia, familial, 1 (5)
-	-	3	not specified (3)
-	-	2	Familial hypercholesterolemia (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	2.5
DANN	Benign	0.63
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	-0.57	N
PhyloP100		0.11
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.12	N
REVEL	Pathogenic	0.74
Sift	Benign	0.90	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.84
MPC		0.18
ClinPred		0.026	T
GERP RS		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.93
Mutation Taster		=2/98	disease causing

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: rs555292896; hg19: chr19-11230789; COSMIC: COSV52942805;