rs879255197

Variant names:

• chr19-11129519-TCGTCTTCCTTTGCCTG-T
• rs879255197
• NM_000527.5:c.2397_2412delCGTCTTCCTTTGCCTG

Variant summary

Our verdict is Likely pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PVS1

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.2397_2412del (p.Val800fs) variant is classified as Likely Pathogenic, for Familial Hypercholesterolemia by applying evidence code PM2 and PVS1 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).. PSV1: Deletion of 16 bp causing an out-of-frame consequence (Exon 17) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585851/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 4.94
• Publications: 0 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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2397_2412delCGTCTTCCTTTGCCTG	p.Val800GlyfsTer124	frameshift	Exon 17 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2397_2412delCGTCTTCCTTTGCCTG	p.Val800GlyfsTer122	frameshift	Exon 17 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2274_2289delCGTCTTCCTTTGCCTG	p.Val759GlyfsTer124	frameshift	Exon 16 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2397_2412delCGTCTTCCTTTGCCTG	p.Val800GlyfsTer124	frameshift	Exon 17 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2655_2670delCGTCTTCCTTTGCCTG	p.Val886GlyfsTer124	frameshift	Exon 17 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2397_2412delCGTCTTCCTTTGCCTG	p.Val800GlyfsTer122	frameshift	Exon 17 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Hypercholesterolemia, familial, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

Splicing

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

Other links and lift over

dbSNP: rs879255197; hg19: chr19-11240195;