19-11102792-T-C

Position:

• chr19-11102792-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS3_Supporting PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.313+6T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Brome criteria for possible FH after alternative causes of high cholesterol were excluded, reported by Bourbon et al from Unidade de Investigação Cardiovascular, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal (PMID 19411563).PS3_Supporting: Level 3 experiment, heterozygous patients’ lymphocytes were used for RNA assay and exon 3 skipping (p.Leu64_Pro105delinsSer) was observed, reported by Bourbon et al (PMID 19411563). PM3 not met: This variant is identified in an index case with one other variant, LDLR c.1291G>A (p.Ala431Thr), classified as Pathogenic by these guidelines, in trans, reported by Bourbon et al (PMID 19411563).However, patient’s untreated LDL-C is 435mg/dl, which is under 500mg/dl, therefore PM3 is not met.PP1 not met: Variant segregates with FH phenotype in 1 (less than 2) informative meiosis from 1 family who was tested positive for the variant with LDL-C > 75th percentile, reported by Bourbon et al (PMID 19411563). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584845/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_001406861.1 missense
• Scores: Splicing: ADA: 0.9746
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 1.71

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.313+6T>C		splice_region_variant, intron_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.313+6T>C		splice_region_variant, intron_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/208 non-FH alleles -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 26, 2022	The NM_000527.5 (LDLR):c.313+6T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Brome criteria for possible FH after alternative causes of high cholesterol were excluded, reported by Bourbon et al from Unidade de Investigação Cardiovascular, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal (PMID 19411563). PS3_Supporting: Level 3 experiment, heterozygous patients’ lymphocytes were used for RNA assay and exon 3 skipping (p.Leu64_Pro105delinsSer) was observed, reported by Bourbon et al (PMID 19411563). PM3 not met: This variant is identified in an index case with one other variant, LDLR c.1291G>A (p.Ala431Thr), classified as Pathogenic by these guidelines, in trans, reported by Bourbon et al (PMID 19411563).However, patient’s untreated LDL-C is 435mg/dl, which is under 500mg/dl, therefore PM3 is not met. PP1 not met: Variant segregates with FH phenotype in 1 (less than 2) informative meiosis from 1 family who was tested positive for the variant with LDL-C > 75th percentile, reported by Bourbon et al (PMID 19411563). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.060		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: rs879254468; hg19: chr19-11213468;