chr19-11105556-ATGG-A

Variant names:

• chr19-11105556-ATGG-A
• rs121908027
• NM_000527.5:c.654_656delTGG

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM4_Supporting PP5_Very_Strong

The NM_000527.5(LDLR):​c.654_656delTGG​(p.Gly219del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000188 in 1,595,642 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002568106: PS3_moderate - PMID:2088165 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: <2% LDLR activity. PMID:2088165; SCV002764421: Functional studies demonstrate significantly reduced LDLR activity [PMID:2088165].; SCV004820190: Functional studies have shown that this variant causes defective protein transport to the Golgi complex (PMID:2088165) and the mutant protein shows <2% LDLR activity in cells from a homozygous individual (http://www.ucl.ac.uk/ldlr/).; SCV000577590: Published functional studies demonstrate a damaging effect with slow processing and abnormal rate of transport to the Golgi complex likely due to protein misfolding (Hobbs et al., 1990); SCV000925137: Functional studies of this variant show that it's a class II mutation that results in impaired intracellular transport and processing of the LDL receptor protein between the endoplasmic reticulium and Golgi complex (Hobbs, et al, 1990).; SCV001469534: Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID:2088165 (1990)).; SCV000909143: Functional studies have shown that this variant causes defective protein transport to the Golgi complex (PMID:2088165) and the mutant protein shows <2% LDLR activity in cells from a homozygous individual (http://www.ucl.ac.uk/ldlr/).; SCV002658972: Functional studies have indicated impaired protein transport and processing (Hobbs HH et al, Annu. Rev. Genet. 1990; 24:133-70; Hobbs HH et al. Hum Mutat, 1992;1:445-66).; SCV004847786: In vitro functional studies support an impact on protein function (Hobbs 1990).".

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: LDLR NM_000527.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:29
• Conservation: PhyloP100: 4.96
• Publications: 13 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002568106: PS3_moderate - PMID: 2088165 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: <2% LDLR activity. PMID: 2088165; SCV002764421: Functional studies demonstrate significantly reduced LDLR activity [PMID:2088165].; SCV004820190: Functional studies have shown that this variant causes defective protein transport to the Golgi complex (PMID: 2088165) and the mutant protein shows <2% LDLR activity in cells from a homozygous individual (http://www.ucl.ac.uk/ldlr/).; SCV000577590: Published functional studies demonstrate a damaging effect with slow processing and abnormal rate of transport to the Golgi complex likely due to protein misfolding (Hobbs et al., 1990); SCV000925137: Functional studies of this variant show that it's a class II mutation that results in impaired intracellular transport and processing of the LDL receptor protein between the endoplasmic reticulium and Golgi complex (Hobbs, et al, 1990).; SCV001469534: Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 2088165 (1990)).; SCV000909143: Functional studies have shown that this variant causes defective protein transport to the Golgi complex (PMID: 2088165) and the mutant protein shows <2% LDLR activity in cells from a homozygous individual (http://www.ucl.ac.uk/ldlr/).; SCV002658972: Functional studies have indicated impaired protein transport and processing (Hobbs HH et al, Annu. Rev. Genet. 1990; 24:133-70; Hobbs HH et al. Hum Mutat, 1992;1:445-66).; SCV004847786: In vitro functional studies support an impact on protein function (Hobbs 1990).
• PM1: In a hotspot region, there are 40 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_000527.5
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-11105556-ATGG-A is Pathogenic according to our data. Variant chr19-11105556-ATGG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 226329.Status of the report is reviewed_by_expert_panel, 3 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.654_656delTGG	p.Gly219del	disruptive_inframe_deletion	Exon 4 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.654_656delTGG	p.Gly219del	disruptive_inframe_deletion	Exon 4 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.531_533delTGG	p.Gly178del	disruptive_inframe_deletion	Exon 3 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.654_656delTGG	p.Gly219del	disruptive_inframe_deletion	Exon 4 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.912_914delTGG	p.Gly305del	disruptive_inframe_deletion	Exon 4 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.654_656delTGG	p.Gly219del	disruptive_inframe_deletion	Exon 4 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151336 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250684 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1444306 Hom.: 0 AF XY: 0.0000292 AC XY: 21 AN XY: 718064

African (AFR) AF: 0.00 AC: 0 AN: 32964

American (AMR) AF: 0.00 AC: 0 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.000706 AC: 18 AN: 25500

East Asian (EAS) AF: 0.00 AC: 0 AN: 38464

South Asian (SAS) AF: 0.00 AC: 0 AN: 86006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00000454 AC: 5 AN: 1101198

Other (OTH) AF: 0.0000676 AC: 4 AN: 59206

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151336 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73924

African (AFR) AF: 0.00 AC: 0 AN: 41320

American (AMR) AF: 0.00 AC: 0 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67852

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
16	-	-	Hypercholesterolemia, familial, 1 (16)
6	-	-	not provided (6)
5	-	-	Familial hypercholesterolemia (5)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121908027; hg19: chr19-11216232;