NM_000527.5:c.1436T>A

Variant names:

• chr19-11113612-T-A
• rs879254900
• NM_000527.5:c.1436T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP1_Moderate PM2 PM3 PS4_Supporting PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1436T>A (p.Leu479Gln) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PP1_Moderate, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines specification version 1.2) on 23 February 2024.The supporting evidence is as follows: PM2: This variant is absent from gnomAD v4.0.0.PP3: REVEL= 0.938.PS4_Supporting, PP4: Identified in two index cases who fulfil FH criteria, reported in PMID 33732287 (Moradi et al., 2021; LDLC 391 mg/dl at age of 24 years) and PMID 29213121 (Fairoozy et al., 2017; LDL-C 15 mmol/L at age of 15 years). Both index cases are homozygous for the variant.PP1_Moderate: Variant segregates with FH phenotype in five informative meiosis in two families, the affected relatives are positive for the variant, reported in PMID 33732287 and 29213121.PM3: Variant observed in a true homozygous case who had HoFH phenotype with LDLC of 15 mmol/L, reported in PMID 29213121. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404086021/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.92

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 9 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.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1436T>A	p.Leu479Gln	missense_variant	Exon 10 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1436T>A	p.Leu479Gln	missense_variant	Exon 10 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Feb 23, 2024

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.1436T>A (p.Leu479Gln) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PP1_Moderate, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD v4.0.0. PP3: REVEL= 0.938. PS4_Supporting, PP4: Identified in two index cases who fulfil FH criteria, reported in PMID 33732287 (Moradi et al., 2021; LDLC 391 mg/dl at age of 24 years) and PMID 29213121 (Fairoozy et al., 2017; LDL-C 15 mmol/L at age of 15 years). Both index cases are homozygous for the variant. PP1_Moderate: Variant segregates with FH phenotype in five informative meiosis in two families, the affected relatives are positive for the variant, reported in PMID 33732287 and 29213121. PM3: Variant observed in a true homozygous case who had HoFH phenotype with LDLC of 15 mmol/L, reported in PMID 29213121. -

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Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial hypercholesterolemia Pathogenic:1

Dec 09, 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.1436T>A (p.Leu479Gln) results in a non-conservative amino acid change located in the LDL-receptor class B (LDLRB) repeat profile domain (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251198 control chromosomes. c.1436T>A has been reported in the literature in a family affected with Familial Hypercholesterolemia where the affected proband was homozygous for the variant and his affected parents were heterozygous for the variant. (e.g, Fairoozy_2017, Moradi_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same codon has been classified pathogenic in ClinVar (c.1436T>C (p.Leu479Pro), suggesting it is critical for the protein function. The following publications have been ascertained in the context of this evaluation (PMID: 29213121, 33732287). ClinVar contains an entry for this variant (Variation ID: 992900). Based on the evidence outlined above, the variant was classified as as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;H
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.92	P;.;.;.;.;.
Vest4		0.86
MutPred		0.88		Gain of disorder (P = 0.0522);Gain of disorder (P = 0.0522);.;.;.;Gain of disorder (P = 0.0522);
MVP		1.0
MPC		0.81
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
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

Other links and lift over

dbSNP: rs879254900; hg19: chr19-11224288;