rs776217028

Variant names:

• chr19-11120471-G-A
• rs776217028
• NM_000527.5:c.2089G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11120471-G-A
• chr19-11120471-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.2089G>A (p.Ala697Thr) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: PopMax MAF=0.00002196 in South Asian exomes (gnomAD v4.1.0).PP3: REVEL=0.815. LINK:https://erepo.genome.network/evrepo/ui/classification/CA038513/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 4.28
• 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 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.2089G>A	p.Ala697Thr	missense	Exon 14 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2089G>A	p.Ala697Thr	missense	Exon 14 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1966G>A	p.Ala656Thr	missense	Exon 13 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.2089G>A	p.Ala697Thr	missense	Exon 14 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2347G>A	p.Ala783Thr	missense	Exon 14 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2089G>A	p.Ala697Thr	missense	Exon 14 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251080 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461640 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727128

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

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

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

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.3
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.81
Sift	Benign	0.039	D
Sift4G	Uncertain	0.041	D
Polyphen		0.027	B
Vest4		0.16
MutPred		0.56		Gain of ubiquitination at K693 (P = 0.0582)
MVP		1.0
MPC		0.22
ClinPred		0.24	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.54
gMVP		0.81
Mutation Taster		=1/99	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: rs776217028; hg19: chr19-11231147;