rs879254641

Variant names:

• chr19-11105587-C-CGGACAAATCTGA
• rs879254641
• NM_000527.5:c.682_683insGACAAATCTGAG

Your query was ambiguous. Multiple possible variants found:

• chr19-11105587-CG-CGGACAAATCTGAG
• chr19-11105587-CG-CTCAAGGAAACCCGACTGCA
• chr19-11105587-CG-CTGCA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The ENST00000558518.6(LDLR):​c.682_683insGACAAATCTGAG​(p.Asp227_Glu228insGlyGlnIleTer) variant causes a stop gained, disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E228E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR ENST00000558518.6 stop_gained, disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.88
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-11105587-C-CGGACAAATCTGA is Pathogenic according to our data. Variant chr19-11105587-C-CGGACAAATCTGA is described in ClinVar as Pathogenic. ClinVar VariationId is 440596.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000558518.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.682_683insGACAAATCTGAG	p.Asp227_Glu228insGlyGlnIleTer	stop_gained disruptive_inframe_insertion	Exon 4 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.682_683insGACAAATCTGAG	p.Asp227_Glu228insGlyGlnIleTer	stop_gained disruptive_inframe_insertion	Exon 4 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.559_560insGACAAATCTGAG	p.Asp186_Glu187insGlyGlnIleTer	stop_gained disruptive_inframe_insertion	Exon 3 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.682_683insGACAAATCTGAG	p.Asp227_Glu228insGlyGlnIleTer	stop_gained disruptive_inframe_insertion	Exon 4 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.940_941insGACAAATCTGAG	p.Asp313_Glu314insGlyGlnIleTer	stop_gained disruptive_inframe_insertion	Exon 4 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.682_683insGACAAATCTGAG	p.Asp227_Glu228insGlyGlnIleTer	stop_gained disruptive_inframe_insertion	Exon 4 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs879254641; hg19: chr19-11216263;