rs879254826

chr19-11113287-CCTACCTCTT-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000527.5(LDLR):c.1199_1207del(p.Tyr400_Phe402del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A399A) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
• Consequence: LDLR NM_000527.5 inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:2
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-11113287-CCTACCTCTT-C is Pathogenic according to our data. Variant chr19-11113287-CCTACCTCTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251727.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11113287-CCTACCTCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1199_1207del	p.Tyr400_Phe402del	inframe_deletion	9/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1199_1207del	p.Tyr400_Phe402del	inframe_deletion	9/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 29

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

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:5 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2 Uncertain:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 20, 2023	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. -
Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2018	Variant 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	For 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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.1199_1207delACCTCTTCT pathogenic mutation (also known as p.Y400_F402del) is located in coding exon 9 of the LDLR gene. This pathogenic mutation results from an in-frame ACCTCTTCT deletion at nucleotide positions 1199 to 1207. This results in the in-frame deletion of 3 amino acids at codon 400. This mutation has been detected in numerous individuals with familial hypercholesterolemia, including heterozygous (HeFH) and homozygous (HoFH) cases, and it has been suggested as a founder mutation in the Grand Canary Islands of Spain; furthermore, significant co-segregation with disease has been reported in multiple families (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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254826; hg19: chr19-11223963;