rs879255150

Variant names:

• chr19-11123183-C-G
• rs879255150
• NM_000527.5:c.2150C>G
• LDLR p.Ala717Gly

Variant summary

Our verdict is Uncertain significance. The variant received -2 ACMG points: 2P and 4B. BS3 PM2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2150C>G (p.Ala717Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BS3 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: This variant is absent from gnomAD (gnomAD v4.1.0).BS3: Level 1 assays: PMID 12837857 (Chang et al., 2003); Heterologous cells (COS-7), flow cytometry and Western blot assays showed normal (>90%) expression and LDL particle clearance ---- functional study is consistent with no damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585793/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 30)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 0.632
• 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

Our verdict: Uncertain_significance. The variant received -2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.2150C>G	p.Ala717Gly	missense	Exon 15 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2150C>G	p.Ala717Gly	missense	Exon 15 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2027C>G	p.Ala676Gly	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.2150C>G	p.Ala717Gly	missense	Exon 15 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2408C>G	p.Ala803Gly	missense	Exon 15 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2150C>G	p.Ala717Gly	missense	Exon 15 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	1	Hypercholesterolemia, familial, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.63
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.52
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.67
Mutation Taster		=7/93	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs879255150;

hg19: chr19-11233859;