rs121908030

Variant names:

• chr19-11107484-G-A
• rs121908030
• NM_000527.5:c.910G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11107484-G-A
• chr19-11107484-G-C
• chr19-11107484-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS4 PP1_Strong PM3 PM2 PP3 PP4 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.910G>A (p.Asp304Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3_moderate, PS4, PP1_strong, PM3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001203 (0.01203%) in African/African American genomes (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.883.It is above 0.75, so PP3 is Met.PS3_moderate - 2 Level 2 assays performed by different labs:PMID 2088165:Homozygous patient cells, 125I-LDL assays - result - 5-15% LDLR activity.PMID 6438436:Homozygous patient cells, 125I-LDL assays - result - 5-10% LDLR activity.2 Level 3 assays performed by different labs:PMID 4061492:Heterozygous patient cells, 125I-LDL assays - result - 20-30% LDLR activityPMID 6438436:Heterozygous patient cells, 125I-LDL assays - result - 25-50% LDLR activity---- all functional studies are consistent with damaging effect, so PS3_Moderate is Met.PS4 - Variant meets PM2 and is identified in at least 14 unrelated index cases: 4 index cases who fulfill Simon-Broome criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Malaysia (Al-Khateeb et al, 2011) (PMID:21418584); 1 index case who fulfills modified Simon-Broome criteria for FH (pretreatment LDL-C >95th percentile for age and sex, with (1) tendon xanthoma (proband or first-degree relative) or (2) either first-degree relative with premature CHD (<55 years of age in men or 65 years of age in women) or pretreatment LDL-C >95th percentile for age and sex) from Dallas, TX, USA (Ahmad et al, 2011) (PMID:23064986); 1 index case who fulfils Simon-Broome criteria from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID:17094996); and 1 index case with clinical diagnosis of FH (based on (1) a plasma LDL cholesterol concentration above the 95th percentile for age and sex and (2) the presence of xanthoma or coronary heart disease in the proband or at least one first degree relative with type IIa hypercholesterolemia, xanthoma, or CVD) from France (Amsellem et al, 2002) (PMID:12436241), so PS4 is Met.PP1_strong - Variant segregates with FH phenotype in at least 6 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): 6 affected family members have the variant, so PP1_Strong is Met.PM3 - Variant meets PM2 and is identified in an index case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with homozygous FH phenotype (14.9 mmol/L) and LDLR c.761A>C/p.(Gln254Pro), classified as Likely pathogenic by these guidelines, in trans, so PM3 is Met.PP4 - Variant meets PM2 and is identified in at least 14 unrelated index cases as described in PS4, PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023792/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: 9.81
• Publications: 17 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

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

Our verdict: Pathogenic. The variant received 16 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.
• 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.910G>A	p.Asp304Asn	missense	Exon 6 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.910G>A	p.Asp304Asn	missense	Exon 6 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.787G>A	p.Asp263Asn	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.910G>A	p.Asp304Asn	missense	Exon 6 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1168G>A	p.Asp390Asn	missense	Exon 6 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.910G>A	p.Asp304Asn	missense	Exon 6 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251318 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

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: 0.00000343 AC: 5 AN: 1457672 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725092

African (AFR) AF: 0.000120 AC: 4 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109262

Other (OTH) AF: 0.00 AC: 0 AN: 60096

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151924 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74172

African (AFR) AF: 0.000193 AC: 8 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000133 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
13	-	-	Hypercholesterolemia, familial, 1 (13)
5	-	-	Familial hypercholesterolemia (5)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dyslipidemia (1)
1	-	-	Homozygous familial hypercholesterolemia (1)
1	-	-	Hypercholesterolemia (1)
1	-	-	LDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.88
Sift	Benign	0.060	T
Sift4G	Benign	0.061	T
Polyphen		0.87	P
Vest4		0.89
MVP		1.0
MPC		0.79
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.68
gMVP		0.98
Mutation Taster		=0/100	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: rs121908030; hg19: chr19-11218160;