rs879254826

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS4PM2PP4PM4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM4, 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). The supporting evidence is as follows: PS4: Variant meets PM2 and is identified in 19 unrelated FH index cases (18 with DLCN criteria>=6 from PMID:18243212 (Alonso et al., 2008), and 1 with DLCN criteria from PMID 27784735 (Sánchez-Hernández et al.,2016)). So PS4 is met.PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PM4: Variant meets PM2 and is in frame deletion. So PM4 is met. PP4: Variant meets PM2 and is identified in 19 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585351/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Consequence

LDLR
NM_000527.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:2

Conservation

PhyloP100: 7.92
Variant links:
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]

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ACMG classification

Classification made for transcript

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.
PM4
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
LDLRNM_000527.5 linkuse as main transcriptc.1199_1207delACCTCTTCT p.Tyr400_Phe402del disruptive_inframe_deletion 9/18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.1199_1207delACCTCTTCT p.Tyr400_Phe402del disruptive_inframe_deletion 9/181 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152060
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152060
Hom.:
0
Cov.:
29
AF XY:
0.0000135
AC XY:
1
AN XY:
74248
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Uncertain significance, criteria provided, single submitterresearchFundacion Hipercolesterolemia FamiliarMar 01, 2016- -
Likely pathogenic, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelMar 20, 2023The NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM4, 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). The supporting evidence is as follows: PS4: Variant meets PM2 and is identified in 19 unrelated FH index cases (18 with DLCN criteria>=6 from PMID: 18243212 (Alonso et al., 2008), and 1 with DLCN criteria from PMID 27784735 (Sánchez-Hernández et al.,2016)). So PS4 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PM4: Variant meets PM2 and is in frame deletion. So PM4 is met. PP4: Variant meets PM2 and is identified in 19 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met. -
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 04, 2023For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 21722902, 24507775, 25461735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 251727). This variant is also known as c.1197_2205del9. This variant has been observed in individuals with familial hypercholesterolemia (PMID: 18243212). This variant is not present in population databases (gnomAD no frequency). This variant, c.1199_1207del, results in the deletion of 3 amino acid(s) of the LDLR protein (p.Tyr400_Phe402del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 11, 2018Variant summary: LDLR c.1199_1207delACCTCTTCT (p.Tyr400_Phe402del), also known as c.1197_1205del9, results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant was absent in 276812 control chromosomes (gnomAD). The variant, c.1199_1207delACCTCTTCT, has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, including one homozygote, and is one of the most common variants in the Spanish populations (Alonso_2008, Sanchez-Hernandez_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 14, 2024The c.1199_1207delACCTCTTCT pathogenic mutation (also known as p.Y400_F402del), located in coding exon 9 of the LDLR gene, results from an in-frame ACCTCTTCT deletion at nucleotide positions 1199 to 1207. This results in the in-frame deletion of 3 amino acids from codons 400 to 402. This variant was identified in one or more individuals with features consistent with familial hypercholesterolemia, segregated with disease multiple families, and was proposed as a founder mutation in the Grand Canary Islands of Spain (Mozas P et al. Hum Mutat, 2004 Aug;24:187; Alonso R et al. Atherosclerosis, 2008 Oct;200:315-21; Alonso R et al. J Clin Lipidol 2016 Apr;10:953-961; Sánchez-Hernández RM et al. J Clin Lipidol 2019 May;13:618-626). This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs879254826; hg19: chr19-11223963; API