rs750126678

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

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 (★). Synonymous variant affecting the same amino acid position (i.e. T108T) has been classified as Benign.

• 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

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain LDL-receptor class A 3 (size 38) in uniprot entity LDLR_HUMAN there are 57 pathogenic changes around while only 8 benign (88%) in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.323C>A	p.Thr108Lys	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.323C>A	p.Thr108Lys	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3

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

Uncertain significance, no assertion criteria provided	clinical testing	Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham	Jan 01, 2023	This variant is not present in population databases (gnomAD no frequency). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2022	This variant is not present in population databases (gnomAD no frequency). 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). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 841986). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. -

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
MutationTaster	Benign	0.88	D;D;D;D;D;D;D
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
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.50
gMVP		0.93

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: rs750126678; hg19: chr19-11215905;