19-11105408-G-C

Position:

• chr19-11105408-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.502G>C​(p.Asp168His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D168E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a disulfide_bond (size 17) in uniprot entity LDLR_HUMAN there are 50 pathogenic changes around while only 1 benign (98%) 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 chr19-11105410-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 19-11105408-G-C is Pathogenic according to our data. Variant chr19-11105408-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105408-G-C is described in Lovd as [Pathogenic]. Variant chr19-11105408-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.502G>C	p.Asp168His	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.502G>C	p.Asp168His	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461684 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2020

The p.D168H pathogenic mutation (also known as c.502G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 502. The aspartic acid at codon 168 is replaced by histidine, an amino acid with similar properties. This mutation was first reported (as legacy p.D147H) in multiple families from a Sephardic Jewish hypercholesterolemia cohort, including one family with segregation in multiple affected heterozygous and homozygous cases; in vitro functional studies in homozygous fibroblasts demonstrated significant impact on LDLR trafficking and LDL binding (Leitersdorf E et al. Hum. Genet., 1993 Mar;91:141-7). This mutation has also been reported in additional familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Durst R et al. Atherosclerosis, 2017 02;257:55-63). In addition, alternate amino acid substitutions at this codon, p.D168Y, p.D168N, p.D168A, p.D168E, p.D168G, have also been reported in individuals with FH, indicating this position may be a hotspot location (Christiano AM et al. Am. J. Hum. Genet., 1996 Apr;58:671-81; Day IN et al. Hum. Mutat., 1997;10:116-27; Santos PC et al. Atherosclerosis, 2014 Mar;233:206-10; Sözen MM et al. Atherosclerosis, 2005 May;180:63-71; Chmara M et al. J. Appl. Genet., 2010;51:95-106). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp168 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects LDLR function (PMID: 8462973). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251258). This variant is also known as p.D147H and FH-Sephardic. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 8462973, 16250003, 20828696, 28104544). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 168 of the LDLR protein (p.Asp168His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.87
MutPred		0.95		Loss of disorder (P = 0.0457);Loss of disorder (P = 0.0457);.;Loss of disorder (P = 0.0457);
MVP		1.0
MPC		0.88
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs200727689; hg19: chr19-11216084;