rs730882098

Variant names:

• chr19-11111586-A-C
• rs730882098
• NM_000527.5:c.1133A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11111586-A-C
• chr19-11111586-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4_Moderate PM3 PP1_Moderate PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1133A>C (p.Gln378Pro) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM2, PS4_Moderate, PM3, PP1_Moderate, PP3, and PP4 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: PopMax MAF = 0.00001760 (0.001760%) in European (non-Finnish) exomes (gnomAD v2.1.1).PP3: REVEL = 0.754.PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PS4_moderate: Variant meets PM2 and is identified in at least 6 unrelated index cases: 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome definite criteria; 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6; 1 case from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory with Dutch lipid clinic network >=6; 1 case from South Africa in PMID:9664576; 1 case from Spain in PMID:15241806; 1 case from Italy in PMID:23375686.PM3: PMID:27784735 - variant identified in two children with homozygous FH: in one patient confirmed in trans with LDLR p.Ile792Thr and in the second patient confirmed in trans with a LP/P LDLR exonic deletion; given this exonic deletion is LP/P, PM3 applies.PP4: Variant meets PM2 and is identified in >1 index case who fulfill clinical criteria for FH, after alternative causes of high cholesterol were excluded.Note: BS3 not met: PMID:32015373 - Level 1 assay: Heterologous cells, FACS assays – results - cell surface LDLR (96%), binding (101%) were normal; LDL uptake (80%) activity is not above 90%, so BS3 not met. This result suggests this variant may only have a minor effect (i.e. 20% reduction in LDL uptake), although this is not insignificant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023422/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:14 U:3 O:1
• Conservation: PhyloP100: 9.11
• Publications: 5 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_pathogenic. The variant received 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1133A>C	p.Gln378Pro	missense	Exon 8 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1133A>C	p.Gln378Pro	missense	Exon 8 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1010A>C	p.Gln337Pro	missense	Exon 7 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.1133A>C	p.Gln378Pro	missense	Exon 8 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1391A>C	p.Gln464Pro	missense	Exon 8 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1133A>C	p.Gln378Pro	missense	Exon 8 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251308 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461580 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727108

African (AFR) AF: 0.00 AC: 0 AN: 33474

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

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

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111880

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000838 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	3	-	Hypercholesterolemia, familial, 1 (9)
5	-	-	Familial hypercholesterolemia (5)
1	-	-	Cardiovascular phenotype (1)
1	-	-	LDLR-related disorder (1)
1	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.6	L
PhyloP100		9.1
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.15	B
Vest4		0.59
MutPred		0.66		Gain of catalytic residue at Q378 (P = 0.0223)
MVP		1.0
MPC		0.44
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.99
Mutation Taster		=3/97	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: rs730882098; hg19: chr19-11222262;