rs879254821

Positions:

• chr19-11111644-G-A
• chr19-11111644-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP4 PS3_Moderate PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1186+5G>A variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PS3_moderate - Level 2 FS: PMID:21990180 - study on htz patient's lymhocytes. FACS + CSLM + Nothern blot were used. 50% biosynthetic process; 65% binding; 60% clearance. Abnormal transcript: retention of part of intron 8 causing a frameshift and premature stop codon (LDLR:p.G396fs*26) then identified by cDNA sequencing.PS4_moderate - Variant meets PM2 and was found in 8 unrelated FH cases.PP4 - Variant meets PM2. Variant found in 8 FH cases fulfilling validated clinical criteria. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585344/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:2
• Conservation: PhyloP100: 5.28

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.1186+5G>A		splice_donor_5th_base_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.1186+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4 Uncertain:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 08, 2021	The NM_000527.5(LDLR):c.1186+5G>A variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PS3_moderate - Level 2 FS: PMID:21990180 - study on htz patient's lymhocytes. FACS + CSLM + Nothern blot were used. 50% biosynthetic process; 65% binding; 60% clearance. Abnormal transcript: retention of part of intron 8 causing a frameshift and premature stop codon (LDLR:p.G396fs*26) then identified by cDNA sequencing. PS4_moderate - Variant meets PM2 and was found in 8 unrelated FH cases. PP4 - Variant meets PM2. Variant found in 8 FH cases fulfilling validated clinical criteria. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

Familial hypercholesterolemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 04, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 251706). This variant is also known as IVS8+5G>A. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 18096825, 23833242, 26342331, 33740630; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2020	Variant summary: LDLR c.1186+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site, one predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Etxebarria_2012). The variant was absent in 249224 control chromosomes (gnomAD). c.1186+5G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Etxebarria_2012, Amsellem_2002, Minicocci_2015, Kusters_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant causes decreased expression, LDL binding, and LDL internalization (Etxebarria_2012). Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as pathogenic (1x) / likely pathogenic (2x), or VUS (2x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	34
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: -9
DS_DL_spliceai		0.60		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879254821; hg19: chr19-11222320;