rs121908038

Variant names:

• chr19-11113293-T-A
• rs121908038
• NM_000527.5:c.1202T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 7.92
• Publications: 14 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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain 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 chr19-11113292-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 161267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• 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 VariationId is 3735.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1202T>A	p.Leu401His	missense_variant	Exon 9 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1202T>A	p.Leu401His	missense_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460990 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726812

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 29

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

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

- -

Oct 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 12, 2024

Department of Human Genetics, Hannover Medical School

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypercholesterolemia Pathogenic:1 Uncertain:1

Jul 25, 2024

Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Nov 07, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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. This variant is not present in population databases (ExAC no frequency). 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 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

May 21, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 25, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;M
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
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	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.89
gMVP		0.99
Mutation Taster		=0/100	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: rs121908038; hg19: chr19-11223969;