rs121908038

Positions:

chr19-11113293-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000527.5(LDLR):c.1202T>A(p.Leu401His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L401V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 7.92

Variant links:

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 links:

LDLR (HGNC:):

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a strand (size 4) in uniprot entity LDLR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 19-11113293-T-A is Pathogenic according to our data. Variant chr19-11113293-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3735.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=3}. Variant chr19-11113293-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1202T>A	p.Leu401His	missense_variant	9/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1202T>A	p.Leu401His	missense_variant	9/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460990

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726812

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1995	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Jun 12, 2024	- -

Familial hypercholesterolemia

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2019	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu401¬†amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 21722902, 25461735,¬†24507775). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 7573037, 19843101, 15701167, 11810272). This variant is also known as p.Leu380His or FH-Pori in the literature. ClinVar contains an entry for this variant (Variation ID: 3735). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with histidine at codon 401 of the LDLR protein (p.Leu401His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine. -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	Jul 25, 2024	Based on the ACMG/AMP 2015 guidelines (Richards 2015), p.Leu401His variant has the following pathogenicity criteria: PM1- located in the EGF-precursor homology domain: YWTD repeat (Galicia-Garcia 2020); PM2 - detected in control samples of gnomAD v4.1.0 with a frequency of 0.0002480%; PM5 - missense variant at the same codon as a variant classified as pathogenic (c.1201С>G, p.Leu401Val (ClinVar ID 161267)) and predicts a different amino acid change; PP1_Strong - segregated with FH in 6 family members in three generations, including several family members in one generation (data from the Laboratory of Molecular Genetics, Moscow, Russia ); PP3; PP4-registered in patients with FH. According to the ClinGen guidelines for LDLR variant classification (Chora 2022): PS4 - variant has been found in ≥10 unrelated FH cases, including 28 FH case in Russia (Meshkov 2021); PM2 - has a PopMax MAF ≤ 0.0002 (0.02%) in gnomAD (0.0002480% v4.1.0 gnomAD); PM5 - missense variant at the same codon as a variant classified as pathogenic (c.1201С>G, p.Leu401Val (ClinVar ID 161267)) and predicts a different amino acid change; PP1_Strong -segregates with phenotype in 6 informative meioses in 1 family (5 relatives with this variant (LDL-C level >75th percentile) and 1 relative without this variant (LDL-C level<75th percentile); PP3 - REVEL score 0.952 (Liu 2011, Liu 2020); PP4 - identified in 28 proband with FH based on DLCN-criteria (data from the Laboratory of Molecular Genetics, Moscow, Russia (Meshkov 2021)). Based on a combination of criteria, this variant is pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L380H), FH-Pori; This variant is associated with the following publications: (PMID: 7573037, 19843101, 38245461, 33391333, 21310417, 38255840, 35928446, 11810272, 15523646, 36644564, 38203485, 33418990, 34834584, 37808210, 15701167, 33955087, 34037665, 33269076, 30270359, Urazgildeeva2023[CaseReport]) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The p.L401H pathogenic mutation (also known as c.1202T>A), located in coding exon 9 of the LDLR gene, results from a T to A substitution at nucleotide position 1202. The leucine at codon 401 is replaced by histidine, an amino acid with similar properties. This alteration (also referred to as L380H and FH-Pori), has been detected in several unrelated individuals with familial hypercholesterolemia (FH) and in FH cohorts (Koivisto UM et al. Am. J. Hum. Genet. 1995;57:789-97; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Zakharova FM et al. BMC Med. Genet. 2005;6:6; Alver M et al. Genet Med. 2019 05;21(5):1173-1180; Meshkov A et al. Genes (Basel). 2021 01;12(1)). Another alteration at the same codon, p.L401V (c.1201C>G), has also been reported in association with FH (Leren TP et al. J. Intern. Med. 1997;241:185-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.93

D;.;.;.;.;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;.;.;.;.;M

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.8

D;D;D;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.89

MutPred

0.92

Loss of stability (P = 0.0316);Loss of stability (P = 0.0316);.;.;.;Loss of stability (P = 0.0316);

MVP

1.0

MPC

0.91

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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