NM_000527.5:c.2320G>T

Variant names:

• chr19-11128016-G-T
• rs138190838
• NM_000527.5:c.2320G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000527.5(LDLR):​c.2320G>T​(p.Asp774Tyr) 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 (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.484

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2320G>T	p.Asp774Tyr	missense_variant	Exon 16 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2320G>T	p.Asp774Tyr	missense_variant	Exon 16 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypercholesterolemia Uncertain:1

Aug 23, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with tyrosine at codon 774 of the LDLR protein (p.Asp774Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of familial hypercholesterolemia (Invitae). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Asp774 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 24507775), which suggests that this may be a clinically significant amino acid residue. 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	0.11
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	3.7
DANN	Benign	0.87
DEOGEN2	Uncertain	0.60	D;.;.;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.86	D;T;D;D;T;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.012	D;D;D;D;T;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D
Polyphen		0.23	B;.;.;.;.;.
Vest4		0.47
MutPred		0.51		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;.;.;Gain of sheet (P = 0.0125);
MVP		1.0
MPC		0.70
ClinPred		0.35	T
GERP RS		1.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.11
gMVP		0.89

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: rs138190838; hg19: chr19-11238692;