19-11120144-G-T

Variant names:

• chr19-11120144-G-T
• rs754536745
• NM_000527.5:c.1898G>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.1898G>T​(p.Arg633Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R633H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.13
• Publications: 7 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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11120144-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226380.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 19-11120144-G-T is Pathogenic according to our data. Variant chr19-11120144-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 252107.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1898G>T	p.Arg633Leu	missense	Exon 13 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1898G>T	p.Arg633Leu	missense	Exon 13 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1775G>T	p.Arg592Leu	missense	Exon 12 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.1898G>T	p.Arg633Leu	missense	Exon 13 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2156G>T	p.Arg719Leu	missense	Exon 13 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1898G>T	p.Arg633Leu	missense	Exon 13 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Familial hypercholesterolemia Pathogenic:1

Feb 03, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1898G>T (p.Arg633Leu) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). c.1898G>T has been reported in the literature in multiple Dutch individuals affected with Familial Hypercholesterolemia (FH) (e.g. Fouchier_2005, Huijgen_2010, Huijgen_2012, van de rGraaf_2011, Kusters_2013). The JoJoGenetics database reports the variant in 41 patients known in the Netherlands (status June 2019), without providing further information. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense substitutions affecting the same amino acid residue (i.e. p.Arg633Cys, p.Arg633His) have been reported to be deleterious (internal testing and ClinVar), suggesting that the Arg633 is important for protein function. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.1
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.71
MutPred		0.94		Gain of sheet (P = 0.0344)
MVP		1.0
MPC		0.89
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: 9

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

Other links and lift over

dbSNP: rs754536745; hg19: chr19-11230820;