chr19-11089513-T-G

Variant names:

• chr19-11089513-T-G
• rs879254378
• NM_000527.5:c.-36T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP4 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.-36T>G variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PP4: Variant meets PM2, and is identified in one index case who fulfils DLCN criteria for probable FH after alternative causes of high cholesterol were excluded, reported in PMID 21538688 (Supplementary Table 2) by De Castro-Oros et al, 2011 from Universidad de Zaragoza, Spain.BS3_Supporting: Level 3 assay performed with luciferase reporter gene assay in HepG2 cells and there was no significant deference observed in gene expression comparing to wild-type construct, reported in PMID 21538688 by De Castro-Oros et al, 2011 from Universidad de Zaragoza, Spain. Level 3 assay performed with luciferase reporter gene assay in HepG2 cells showed 100% expression compared to wild-type, reported in PMID 31395865 by Kircher et al, 2019 from University of Washington, Seattle, USA. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584714/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: -0.349
• Publications: 3 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]

ENSG00000307752 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.-36T>G		5_prime_UTR	Exon 1 of 18	NP_000518.1
	LDLR-AS1	NR_163945.1		n.147A>C		non_coding_transcript_exon	Exon 1 of 1
	LDLR	NM_001195798.2		c.-36T>G		5_prime_UTR	Exon 1 of 18	NP_001182727.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.-36T>G		5_prime_UTR	Exon 1 of 18	ENSP00000454071.1
	LDLR	ENST00000558013.5	TSL:1	c.-36T>G		5_prime_UTR	Exon 1 of 18	ENSP00000453346.1
	LDLR	ENST00000557958.1	TSL:2	n.51T>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2 Benign:1

Oct 28, 2024

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5 (LDLR):c.-36T>G variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP4: Variant meets PM2, and is identified in one index case who fulfils DLCN criteria for probable FH after alternative causes of high cholesterol were excluded, reported in PMID 21538688 (Supplementary Table 2) by De Castro-Oros et al, 2011 from Universidad de Zaragoza, Spain. BS3_Supporting: Level 3 assay performed with luciferase reporter gene assay in HepG2 cells and there was no significant deference observed in gene expression comparing to wild-type construct, reported in PMID 21538688 by De Castro-Oros et al, 2011 from Universidad de Zaragoza, Spain. Level 3 assay performed with luciferase reporter gene assay in HepG2 cells showed 100% expression compared to wild-type, reported in PMID 31395865 by Kircher et al, 2019 from University of Washington, Seattle, USA.

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.6
DANN	Benign	0.69
PhyloP100		-0.35
PromoterAI		-0.098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs879254378; hg19: chr19-11200189;