rs372828849

Variant names:

• chr19-11102743-T-A
• rs372828849
• NM_000527.5:c.270T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11102743-T-A
• chr19-11102743-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PS4_Supporting PP3 PP4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence PP1_Strong, PM2, PM5, PP3, PP4 and PS4_Supporting 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: PP1_strong - variant segregates with FH phenotype in 11 informative meiosis from 2 families from PMID 20809525 (Marduel et al., 2010): F1: 4 affected relatives have the variant and 3 unaffected relatives do not have the variant; F2: 3 affected relatives have the variant and 1 unaffected relative does not have the variant, so PP1_Strong is met.PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 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.269A>G (p.Asp90Gly) - Pathogenic by these guidelinesThere is 1 variant classified as Pathogenic by these guidelines, so PM5 is met.PP3 - REVEL = 0.833. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 4 index cases with SB criteria of FH (total and LDL-cholesterol levels above the 95th percentile of a sex and age-matched French population and autosomal dominant transmission of hypercholesterolemia in the family) from PMID 20809525 (Marduel et al., 2010), so PP4 is met.PS4_supporting - variant meets PM2 and was identified in 4 index cases with SB criteria of FH from PMID 20809525 (Marduel et al., 2010), (see PP4 for details), so PS4_Supporting is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584821/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: -0.799

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 11 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.
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.270T>A	p.Asp90Glu	missense_variant	Exon 3 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.270T>A	p.Asp90Glu	missense_variant	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Dec 30, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence PP1_Strong, PM2, PM5, PP3, PP4 and PS4_Supporting 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: PP1_strong - variant segregates with FH phenotype in 11 informative meiosis from 2 families from PMID 20809525 (Marduel et al., 2010): F1: 4 affected relatives have the variant and 3 unaffected relatives do not have the variant; F2: 3 affected relatives have the variant and 1 unaffected relative does not have the variant, so PP1_Strong is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 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.269A>G (p.Asp90Gly) - Pathogenic by these guidelines There is 1 variant classified as Pathogenic by these guidelines, so PM5 is met. PP3 - REVEL = 0.833. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 4 index cases with SB criteria of FH (total and LDL-cholesterol levels above the 95th percentile of a sex and age-matched French population and autosomal dominant transmission of hypercholesterolemia in the family) from PMID 20809525 (Marduel et al., 2010), so PP4 is met. PS4_supporting - variant meets PM2 and was identified in 4 index cases with SB criteria of FH from PMID 20809525 (Marduel et al., 2010), (see PP4 for details), so PS4_Supporting is met. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 , family members = 8 with co-segregation / other mutations at same codon / Software predictions: Damaging -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Apr 03, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D90E pathogenic mutation (also known as c.270T>A), located in coding exon 3 of the LDLR gene, results from a T to A substitution at nucleotide position 270. The aspartic acid at codon 90 is replaced by glutamic acid, an amino acid with highly similar properties. This pathogenic mutation was described in four probands with total cholesterol and LDL-cholesterol levels above the 95th percentile and a family history of hypercholesterolemia. This alteration was found to segregate with disease in multiple individuals ( Marduel M, Hum. Mutat. 2010; 31(11):E1811-24). Other described pathogenic alterations, p.D90A, p.D90G, p.D90N and p.D90Y, have been described in this same codon. Based on the supporting evidence, p.D90E is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 90 of the LDLR protein (p.Asp90Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 27824480; Invitae). ClinVar contains an entry for this variant (Variation ID: 251107). 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 with a positive predictive value of 95%. 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: 9026534, 11857755, 12436241, 12837857, 15823276, 16343504, 21376320, 25962062, 27765764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	6.4
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.;.
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;H;H;H
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.99	D;.;.;.;.
Vest4		0.75
MutPred		0.91		Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);
MVP		1.0
MPC		0.78
ClinPred		1.0	D
GERP RS		-2.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.99
gMVP		0.99

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: rs372828849; hg19: chr19-11213419;