19-11113414-C-G

Position:

• chr19-11113414-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PM5

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1323C>G (p.Ile441Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PM5) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP3 - REVEL = 0.769.It is above 0.75, so PP3 is Met.PM5 - 2 other missense variants in the same codon:- NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) (ClinVar ID: 251783) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) (ClinVar ID: 251782) - VUS by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585401/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 0.301

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1323C>G	p.Ile441Met	missense_variant	9/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1323C>G	p.Ile441Met	missense_variant	9/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461698 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jan 17, 2022	The NM_000527.5(LDLR):c.1323C>G (p.Ile441Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PM5) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.769. It is above 0.75, so PP3 is Met. PM5 - 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) (ClinVar ID: 251783) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) (ClinVar ID: 251782) - VUS by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. -
Likely 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	subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH / Software predictions: Conflicting -

Homozygous familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2018

The p.Ile441Met variant (reported as p.Ile420Met) in LDLR has been reported in 1 individual with hypercholesterolemia (Hobbs 1992). This variant is also reported in ClinVar (Variation ID: 251784), and was absent from large population studies. In vitro functional studies using fibroblasts derived from skin cells of the patient with this variant exhibit a significant impact on LDLR receptor activity (Hobbs 1992). In addition, computational prediction tools and conservation analysis suggest that the p.Ile441Met variant may impact the protein. Furthermore, two other variants at the same amino acid position (p.Ile441Asn and p.Ile441Thr) were identified in several patients with hypercholesterolemia and segregated in affected family members, and in vitro functional studies of both variants reveal an impact to receptor function (Benito-Vicente and Hobbs 1992). This data supports a causative role for the p.Ile441Met variant and suggests that changes at this amino acid position are not tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Ile441Met variant is likely pathogenic. ACMG/AMP Criteria applied: PM5_Strong, PM2, PP3, PS3_Supporting. -

Familial hypercholesterolemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 22, 2019

This variant (also known as p.Ile420Met in the mature protein and as FH Roen) is a missense variant located in the first LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental functional study has shown that patient cells carrying this variant have 5-15% LDLR activity. These cells were from a French individual diagnosed with familial hypercholesterolemia that was apparently compound heterozygous with an unknown second allele (PMID: 1301956). Two other variants at the same amino acid position (p.Ile441Asn and p.Ile441Thr) have been detected in several patients with hypercholesterolemia and segregated in affected family members, and both variants have been shown to be functionally defective (PMID: 1301956, 25741862). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Pathogenic	0.77
Sift	Benign	0.041	D;D;D;D;D;D
Sift4G	Uncertain	0.060	T;D;T;T;T;T
Polyphen		0.84	P;.;.;.;.;.
Vest4		0.31
MutPred		0.94		Loss of catalytic residue at I441 (P = 0.0215);Loss of catalytic residue at I441 (P = 0.0215);.;.;.;Loss of catalytic residue at I441 (P = 0.0215);
MVP		1.0
MPC		0.52
ClinPred		0.64	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5933; hg19: chr19-11224090;