rs747344293

Variant names:

• chr19-11129597-AC-A
• rs747344293
• NM_000527.5:c.2478delC

Your query was ambiguous. Multiple possible variants found:

• chr19-11129597-AC-A
• chr19-11129597-AC-ACC

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.2478delC​(p.Val827SerfsTer102) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005427667: An in vitro functional study using heterologous transfected CHO cells has shown that this variant causes either no detectable LDLR protein, or low levels of LDLR protein that is unable to bind the LDL ligand (PMID:7903864)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P826P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.0920
• 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005427667: An in vitro functional study using heterologous transfected CHO cells has shown that this variant causes either no detectable LDLR protein, or low levels of LDLR protein that is unable to bind the LDL ligand (PMID: 7903864).; SCV000709936: Functional studies show that the c.2478delC variant results in either no detectable LDLR protein, or low levels of LDLR protein that is unable to bind the LDL ligand (Sun et al., 1994).; SCV001214561: Experimental studies have shown that this premature translational stop signal affects LDLR function (PMID: 7903864).; SCV002737489: in vitro studies suggested that it would affect LDLR protein expression or stability (Sun, 1994).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11129597-AC-A is Pathogenic according to our data. Variant chr19-11129597-AC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 252342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2478delC	p.Val827SerfsTer102	frameshift	Exon 17 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2478delC	p.Val827SerfsTer100	frameshift	Exon 17 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2355delC	p.Val786SerfsTer102	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.2478delC	p.Val827SerfsTer102	frameshift	Exon 17 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2736delC	p.Val913SerfsTer102	frameshift	Exon 17 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.2478delC	p.Val827SerfsTer100	frameshift	Exon 17 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hypercholesterolemia, familial, 1 (4)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial hypercholesterolemia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.092
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs747344293; hg19: chr19-11240273;