19-11120126-C-T

Position:

• chr19-11120126-C-T

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.1880C>T​(p.Ala627Val) 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. A627D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.78

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 strand (size 5) in uniprot entity LDLR_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chr19-11120126-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 19-11120126-C-T is Pathogenic according to our data. Variant chr19-11120126-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11120126-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1880C>T	p.Ala627Val	missense_variant	13/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1880C>T	p.Ala627Val	missense_variant	13/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Familial hypercholesterolemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 23, 2023	ClinVar contains an entry for this variant (Variation ID: 252102). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala627 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7903864, 9763532, 21376320, 23158915, 23375686, 25807990, 27206935, 27830735, 28235710, 28502510, 30108616). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This variant is also known as p.Ala606Val. This missense change has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 9763532). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 627 of the LDLR protein (p.Ala627Val). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 17, 2023	This missense variant (also known as p.Ala606Val in the mature protein) replaces alanine with valine at codon 627 in the LDLR type B repeat 6 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in two heterozygous individuals affected with familial hypercholesterolemia (PMID: 9763532; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36325061). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Ala627Thr, is considered to be disease-causing (ClinVar variation ID: 252101), suggesting that alanine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The p.A627V variant (also known as c.1880C>T), located in coding exon 13 of the LDLR gene, results from a C to T substitution at nucleotide position 1880. The alanine at codon 627 is replaced by valine, an amino acid with similar properties. This variant has been reported in subjects with familial hypercholesterolemia (FH), including a subject with features of homozygous FH as a compound heterozygote (Mak YT et al. Arterioscler Thromb Vasc Biol, 1998 Oct;18:1600-5; Cheng XY et al. Zhonghua Nei Ke Za Zhi, 2012 Sep;51:680-2; Kong MX et al. Clin Exp Dermatol, 2015 Oct;40:765-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D
Polyphen		0.98	D;.;.;.;.;.
Vest4		0.81
MutPred		0.93		Loss of catalytic residue at A627 (P = 0.0238);Loss of catalytic residue at A627 (P = 0.0238);.;.;.;Loss of catalytic residue at A627 (P = 0.0238);
MVP		1.0
MPC		0.76
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 27

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

Publications

LitVar

Other links and lift over

dbSNP: rs875989934; hg19: chr19-11230802;