rs879254711

Variant names:

• chr19-11107469-G-A
• rs879254711
• NM_000527.5:c.895G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11107469-G-A
• chr19-11107469-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3_Supporting PM2 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c.895G>A (p.Ala299Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, 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:PM2 Met: PopMAX MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1).PP4 Met: This variant meets PM2 and is identified in > 1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH (1 case from Unidad de Biof´ısica , Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180; 1 case from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain, PMID 19318025).PS3_Supporting Met: Heterozygous patient lymphocytes FACS assays (level 3 functional assay) showed normal cell surface localization, but 50% LDL-LDLR uptake and binding (Etxebarria et al, Unidad de Biof´ısica, Centro Mixto CSIC-UPV/EHU and Departamento de Bioqu´ımica, Universidad del Pa´ıs Vasco, Bilbao, Spain, PMID 21990180).PP3 not met: REVEL score = 0.543, which is below the threshold of 0.75. This variant does not creating de novo acceptor or donor site and is not predicted to alter splicing.PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.895G>T (p.Ala299Ser) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585179/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 0.794
• Publications: 10 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 5 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.895G>A	p.Ala299Thr	missense	Exon 6 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.895G>A	p.Ala299Thr	missense	Exon 6 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.772G>A	p.Ala258Thr	missense	Exon 5 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.895G>A	p.Ala299Thr	missense	Exon 6 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1153G>A	p.Ala385Thr	missense	Exon 6 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.895G>A	p.Ala299Thr	missense	Exon 6 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251388 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458380 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725492

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109700

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	5.3
DANN	Benign	0.74
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	-0.10	N
PhyloP100		0.79
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.54
Sift	Benign	0.40	T
Sift4G	Benign	0.57	T
Polyphen		0.034	B
Vest4		0.22
MutPred		0.52		Gain of disorder (P = 0.0438)
MVP		1.0
MPC		0.21
ClinPred		0.54	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.76
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs879254711; hg19: chr19-11218145;