rs750126678

Variant names:

• chr19-11105229-C-A
• rs750126678
• NM_000527.5:c.323C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11105229-C-A
• chr19-11105229-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000527.5(LDLR):​c.323C>A​(p.Thr108Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T108M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.90
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.323C>A	p.Thr108Lys	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.323C>A	p.Thr108Lys	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Uncertain:2

Jan 01, 2023

Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). -

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 108 of the LDLR protein (p.Thr108Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LDLR-related conditions (PMID: 36229376). ClinVar contains an entry for this variant (Variation ID: 841986). 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 with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D;.;.;.
Eigen	Benign	0.036
Eigen_PC	Benign	0.064
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.1	L;.;.;L
PhyloP100		1.9
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.043	D;D;D;D
Polyphen		0.33	B;.;.;.
Vest4		0.43
MutPred		0.52		Gain of methylation at T108 (P = 0.0014);Gain of methylation at T108 (P = 0.0014);.;Gain of methylation at T108 (P = 0.0014);
MVP		1.0
MPC		0.35
ClinPred		0.67	D
GERP RS		5.3
PromoterAI		-0.0014	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.50
gMVP		0.93
Mutation Taster		=12/88	disease causing

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: rs750126678; hg19: chr19-11215905;