chr19-11089592-T-C

Variant names:

• chr19-11089592-T-C
• rs879254390
• NM_000527.5:c.44T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP4 PS3_Moderate PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.44T>C (p.Leu15Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PP4, and PS4_Supporting 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.PS3_moderate - Level 2 Assay: PMID:27175606: Heterologous cells (CHO), CLSM assays: LDLR retained in ER, no LDL-LDLR binding.LDL binding <70% wild type activity, so PS3_Moderate is met.PS4_supporting - Variant meets PM2 and is identified in - 2 unrelated index cases who fulfill Simon-Broome possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), - 1 case from PMID:12052488 with LDL-C above 10 mmol/L (DLCN>6), from Sweden.3 cases, so PS4_Supporting is met.PP4 - Variant meets PM2 and is identified in 3 unrelated index cases who fulfill FH clinical criteria (see PS4 for details). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584732/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 3.10
• Publications: 6 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-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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.
• 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.44T>C	p.Leu15Pro	missense_variant	Exon 1 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.44T>C	p.Leu15Pro	missense_variant	Exon 1 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460352 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726440

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5176

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111888

Other (OTH) AF: 0.0000166 AC: 1 AN: 60268

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:2

Aug 28, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.44T>C (p.Leu15Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PP4, and PS4_Supporting 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. PS3_moderate - Level 2 Assay: PMID:27175606: Heterologous cells (CHO), CLSM assays: LDLR retained in ER, no LDL-LDLR binding. LDL binding <70% wild type activity, so PS3_Moderate is met. PS4_supporting - Variant meets PM2 and is identified in - 2 unrelated index cases who fulfill Simon-Broome possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), - 1 case from PMID: 12052488 with LDL-C above 10 mmol/L (DLCN>6), from Sweden. 3 cases, so PS4_Supporting is met. PP4 - Variant meets PM2 and is identified in 3 unrelated index cases who fulfill FH clinical criteria (see PS4 for details). -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial hypercholesterolemia Pathogenic:1

Mar 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 15 of the LDLR protein (p.Leu15Pro). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 27175606). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 250981). This variant is also known as L-7P. This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 12052488, 33740630, 33955087; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

not provided Uncertain:1

Aug 22, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with FH in published literature (Lind et al., 2002; Pavlouskova et al., 2016; Leren et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest a damaging effect with retention of LDLR protein in the endoplasmic reticulum and no binding of LDL (Pavlouskova et al., 2016); This variant is associated with the following publications: (PMID: 28379029, 30019023, 28169869, 33740630, 12052488, 27175606, 34037665) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.54	D;.;.;.;.;.
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.083
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.73	T;T;T;T;T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.1	M;.;M;M;M;M
PhyloP100		3.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.12	T;D;D;T;D;T
Sift4G	Uncertain	0.047	D;D;D;D;D;D
Polyphen		0.0050	B;.;.;.;.;.
Vest4		0.71
MutPred		0.67		Loss of stability (P = 0.0193);Loss of stability (P = 0.0193);Loss of stability (P = 0.0193);Loss of stability (P = 0.0193);Loss of stability (P = 0.0193);Loss of stability (P = 0.0193);
MVP		1.0
MPC		0.35
ClinPred		0.58	D
GERP RS		3.7
PromoterAI		-0.081	Neutral
Varity_R		0.51
gMVP		0.95
Mutation Taster		=2/98	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: rs879254390; hg19: chr19-11200268;