19-11102742-A-G

Position:

• chr19-11102742-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5 PM3 PS4 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 ENST00000558518.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 9.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.269A>G	p.Asp90Gly	missense_variant	3/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.269A>G	p.Asp90Gly	missense_variant	3/18	1	NM_000527.5	ENSP00000454071	P3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 8 , family members = 5 with co-segregation / FH-London-4, 15 to 30% LDLR activity / Software predictions: Damaging -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 05, 2008	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Dec 30, 2021	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), UK so 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), UK so PM3 is met PM5 - 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 guidelines There 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 met PP4 - 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 -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	This missense change has been observed in individuals with autosomal dominant or autosomal recessive familial hypercholesterolemia (PMID: 1301956, 9026534, 9259195, 11857755, 12436241, 19837725). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp90 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8347689, 12837857, 15823276, 16343504, 19026292, 20809525, 21376320, 25962062, 27765764, 27824480). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 226313). This variant is also known as p.Asp69Gly. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 90 of the LDLR protein (p.Asp90Gly). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 23, 2022	Variant summary: LDLR c.269A>G (p.Asp90Gly) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). c.269A>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Day_1997, Hooper_2012, Elfatih_2021). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters, including one expert panel (ClinGen FH expert panel), have assessed the variant since 2014: two classified the variant as likely pathogenic, and four (including the expert panel) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 23, 2017

The p.Asp90Gly variant in LDLR has been reported in 5 individuals with familial hypercholesterolemia (FH: 4 in the heterozygous state, 1 in the homozygous state ; Hobbs 1992, Amsellem 2002, Bunn 2002, Do 2015). This variant has also been rep orted in ClinVar (Variation ID# 226313) with one submission (SCV000503124.1) quo ting co-segregation with disease. In vitro functional studies provide some evide nce that the p.Asp90Gly variant may impact protein function (Hobbs 1992). This v ariant has also been identified in 1/66740 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs771019366). T his frequency is low enough to be consistent with the frequency of FH in the gen eral population. Computational prediction tools and conservation analysis sugges t that the p.Asp90Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Other missense variants at t his position have been reported in individuals with hypercholesterolemia (HGMD d atabase, Stenson 2017). In summary, although additional studies are required to fully establish its clinical significance, the p.Asp90Gly variant is likely pat hogenic. ACMG/AMP Criteria applied: PM2; PM5_supporting; PP3; PS3_Supporting; PS 4_Supporting (Richards 2015). -

LDLR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2022

The LDLR c.269A>G variant is predicted to result in the amino acid substitution p.Asp90Gly. This variant is also described using legacy nomenclature as p.Asp69Gly, has been well-documented to be pathogenic for Hypercholesterolemia (Hobbs et al. 1992. PubMed ID: 1301956; Webb et al. 1996. PubMed ID: 9026534; Day et al. 1997. PubMed ID: 9259195; Amsellem et al. 2002. PubMed ID: 12436241; Sturm et al. 2021. PubMed ID: 34037665). This variant have also been interpreted as pathogenic by the Hypercholesterolemia Variant Curation Expert Panel (https://erepo.clinicalgenome.org/evrepo/ui/interpretation/243fe145-86fd-48f6-98dd-c946485388c0). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2023

The c.269A>G (p.D90G) alteration is located in coding exon 3 of the LDLR gene. This alteration results from a A to G substitution at nucleotide position 269, causing the aspartic acid (D) at amino acid position 90 to be replaced by a glycine (G). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, also known as FH London-4 and D69G, has been reported in hypercholesterolemia patients from various ethnic groups (Hobbs, 1992; Webb, 1996; Day, 1997; Bunn, 2002; Amsellem, 2002; Hooper, 2012). Other alterations at the same codon, p.D90N and p.D90E, have also reported in association with hypercholesterolemia (Day, 1997; Marduel, 2010). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is predicted to be structurally disruptive (Kurniawan, 2000). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.4	D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.81
MutPred		0.92		Gain of MoRF binding (P = 0.0706);Gain of MoRF binding (P = 0.0706);Gain of MoRF binding (P = 0.0706);Gain of MoRF binding (P = 0.0706);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs771019366; hg19: chr19-11213418;