19-11102742-A-G

Variant names:

• chr19-11102742-A-G
• rs771019366
• NM_000527.5:c.269A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS4 PM5 PM3 PP1_Moderate PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PP1_Moderate, PM2, PM3, PM5, PP3 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: PS4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH:- 4 unrelated index cases with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia;- at least 1 index case with DLCN probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583646.1), France;- 8 unrelated index cases (7 with DLCN>=6 and 1 SB possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- at least 1 index case with SB criteria for FH (plasma cholesterol of >8.0 mmol/L and family histories of hypercholesterolemia and/or classical clinical stigmata of FH) from PMID 11857755 (Bunn et al., 2002), New Zeland;- 1 index case with SB criteria for FH (grossly increased plasma cholesterol concentration and the presence of xanthomata in childhood and cardiovascular involvement by puberty in the proband, together with hypercholesterolemia in both parents; this index case died at 31years, had cholesterol of 20.7mmol/L and CVD) from PMID 9026534 (Webb et al., 1996), UKso PS4 is met.PP1_moderate - Variant segregates with FH phenotype in 5 informative meiosis from 3 families:- 2 affected family members have the variant, from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA);- 3 affected family members have the variant, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière),so PP1_Moderate is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM3 - variant meets PM2 and was identified in- 1 index case with phenotype of homozygous FH (cholesterol of 20.7mmol/L) and also NM_000527.5(LDLR):c.912C>G (p.Asp304Glu), Likely pathogenic by these guidelines, from PMID 9026534 (Webb et al., 1996), UKso PM3 is metPM5 - 4 other missense variants is the same codon:- NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines- NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelinesThere is 1 variant classified as Pathogenic by these guidelines, so PM5 is met.PP3 - REVEL = 0.957. It is above 0.75, so PP3 is metPP4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH (see PS4 for details), so PP4 is met LINK:https://erepo.genome.network/evrepo/ui/classification/CA042622/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 9.28
• Publications: 9 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 14 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.
• PM5: 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.269A>G	p.Asp90Gly	missense	Exon 3 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.269A>G	p.Asp90Gly	missense	Exon 3 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195800.2		c.269A>G	p.Asp90Gly	missense	Exon 3 of 16	NP_001182729.1	P01130-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.269A>G	p.Asp90Gly	missense	Exon 3 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.527A>G	p.Asp176Gly	missense	Exon 3 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.269A>G	p.Asp90Gly	missense	Exon 3 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727144

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111870

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

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Hypercholesterolemia, familial, 1 (7)
2	-	-	Familial hypercholesterolemia (2)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Homozygous familial hypercholesterolemia (1)
1	-	-	LDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.3
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.92		Gain of MoRF binding (P = 0.0706)
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		1.0
gMVP		1.0
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: rs771019366; hg19: chr19-11213418;