rs745343524

Variant names:

• chr19-11113392-C-A
• rs745343524
• NM_000527.5:c.1301C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11113392-C-A
• chr19-11113392-C-G
• chr19-11113392-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PS4_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PM5, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met.PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PM5: 3 other missense variants in the same codon:- NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines- NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585392/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 B:1
• Conservation: PhyloP100: 1.05

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

Verdict is Likely_pathogenic. Variant got 6 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.
• 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.1301C>A	p.Thr434Lys	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.1301C>A	p.Thr434Lys	missense_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461688 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727146

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: Likely pathogenic

Submissions summary: Pathogenic:4 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Benign:1

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 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.1301C>A (p.Thr434Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, PM5, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated cases, as follows: 1 case with DLCN >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with clinical criteria based on Defesche J. 2000. Familial hypercholesterolemia. In: Betteridge J (ed): Lipids and Vascular Disease from PMID 11810272. So PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)(ClinVar ID 496018) - Unknown significance by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon with clinical DLCN Criteria score ≥ 6, after alternative causes of high cholesterol were excluded. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

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Familial hypercholesterolemia Pathogenic:1

Aug 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1301C>A (p.Thr434Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251262 control chromosomes. c.1301C>A has been reported in the literature in an individual affected with Familial Hypercholesterolemia (Hobbs_1992, Fouchier_2001). This variant has also been reported in several heterozygous individual with familial hypercholesterolemia without clear clinical and family information for assessment (Marco-Bened_2021, Reijman_2023). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1301C>G, p.Thr434Arg), supporting the critical relevance of codon 434 to LDLR protein function. One publication reports that LDL receptor activity in the patient carrying this variant is 5-15% of wild type protein activity. (Hobbs_1992). The following publications have been ascertained in the context of this evaluation (PMID: 1301956, 11810272, 34456049, 36752612). ClinVar contains an entry for this variant (Variation ID: 251773). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.56	D;.;.;.;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	-0.34	N;.;.;.;.;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.017	D;D;D;D;D;D
Sift4G	Benign	0.078	T;T;T;T;T;T
Polyphen		0.20	B;.;.;.;.;.
Vest4		0.37
MutPred		0.90		Loss of catalytic residue at T434 (P = 0.0047);Loss of catalytic residue at T434 (P = 0.0047);.;.;.;Loss of catalytic residue at T434 (P = 0.0047);
MVP		0.99
MPC		0.34
ClinPred		0.34	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.98

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: rs745343524; hg19: chr19-11224068;