NM_000527.5:c.2149G>A

Variant names:

• chr19-11123182-G-A
• rs875989939
• NM_000527.5:c.2149G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2149G>A (p.Ala717Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: PopMax MAF = 0.00002229 (0.002229%) in East Asian exomes (gnomAD v4.1.0).BP4: REVEL = 0.384, it is below 0.50, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant does not create AG/GT. C) there is a AG nearby.MES scores: variant cryptic = -16.32. wt cryptic = -14.92. Canonical acceptor = 8.76. De novo score is negative, so it is not used. Variant is not predicted to alter splicing. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576330/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: -2.65
• Publications: 3 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2149G>A	p.Ala717Thr	missense	Exon 15 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2149G>A	p.Ala717Thr	missense	Exon 15 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.2026G>A	p.Ala676Thr	missense	Exon 14 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2149G>A	p.Ala717Thr	missense	Exon 15 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2407G>A	p.Ala803Thr	missense	Exon 15 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2149G>A	p.Ala717Thr	missense	Exon 15 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	-	Hypercholesterolemia, familial, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.0080
DANN	Benign	0.77
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.14	N
PhyloP100		-2.7
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.72	N
REVEL	Uncertain	0.38
Sift	Benign	0.82	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.28		Gain of glycosylation at A717 (P = 0.101)
MVP		0.97
MPC		0.20
ClinPred		0.063	T
GERP RS		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.64
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs875989939; hg19: chr19-11233858;