NM_000527.5:c.2231G>A

Variant names:

• chr19-11123264-G-A
• rs137853963
• NM_000527.5:c.2231G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PS3_Supporting BP4 BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.2231G>A (p.Arg744Gln) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BP4, BP2 and PS3_supporting 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 - REVEL score is 0.291. It is below 0.5, so splicing evaluation is required. Functional data on splicing is not available. A) Variant not on limits. B) Variant is exonic and within range, but it does not create a de novo AG or GT site. The variant is not predicted to alter splicing.BP2 - 2 individuals from Ambry Genetics: Patient 1 has LDLR p.Gln33* in trans. Phenotype LDL 111 mg/dl (on treatment); Patient 2 has LDLR p.Gly373Asp in trans. Phenotype = "high chol".PS3_supporting - level 3 assay (PMID:9409298) - Heterozygous patients' lymphoblasts, immunoblotting, I125-LDL assay: no precursor detectable, degradation of 125I-LDL = 73%.Variant has 2 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Supporting 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/CA023651/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00096 (3 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:1 B:21 O:2
• Conservation: PhyloP100: -2.23
• Publications: 14 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: Likely_benign. The variant received -1 ACMG points.

• PS3: 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.2231G>A	p.Arg744Gln	missense	Exon 15 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2231G>A	p.Arg744Gln	missense	Exon 15 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2108G>A	p.Arg703Gln	missense	Exon 14 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.2231G>A	p.Arg744Gln	missense	Exon 15 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2489G>A	p.Arg830Gln	missense	Exon 15 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2231G>A	p.Arg744Gln	missense	Exon 15 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152084 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000855 AC: 215 AN: 251340 AF XY: 0.000942

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000959 AC: 1402 AN: 1461766 Hom.: 3 Cov.: 31 AF XY: 0.000942 AC XY: 685 AN XY: 727196

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86256

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53374

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00107 AC: 1188 AN: 1111954

Other (OTH) AF: 0.000762 AC: 46 AN: 60388

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152200 Hom.: 0 Cov.: 30 AF XY: 0.000591 AC XY: 44 AN XY: 74414

African (AFR) AF: 0.000217 AC: 9 AN: 41538

American (AMR) AF: 0.000852 AC: 13 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000985 Hom.: 2

Bravo AF: 0.000654

ExAC AF: 0.000815 AC: 99

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	11	Hypercholesterolemia, familial, 1 (13)
-	-	6	not provided (8)
-	-	2	Familial hypercholesterolemia (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.042
DANN	Benign	0.70
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.2
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.29
Sift	Benign	0.60	T
Sift4G	Benign	0.48	T
Polyphen		0.0010	B
Vest4		0.037
MVP		0.97
MPC		0.24
ClinPred		0.0012	T
GERP RS		-6.8
Varity_R		0.017
gMVP		0.60
Mutation Taster		=80/20	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137853963; hg19: chr19-11233940;