chr19-11123324-T-G

Variant names:

• chr19-11123324-T-G
• rs759440817
• NM_000527.5:c.2291T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2291T>G (p.Ile764Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025.The supporting evidence is as follows: PM2: Variant is absent from gnomAD v4.1.0BP4: REVEL = 0.433, it is below 0.50, so splicing evaluation required. Functional data on splicing not available. A) not on limits.B) Variant does not create GT.C) There is a GT nearby.MES scores: variant cryptic = -7.17, wt cryptic = -8.16, canonical donor site = 9.06.Cryptic scores are negative, splice site not used. Variant is not predicted to alter splicing. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404095729/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.72

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 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2291T>G	p.Ile764Arg	missense_variant	Exon 15 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2291T>G	p.Ile764Arg	missense_variant	Exon 15 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461830 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypercholesterolemia Uncertain:2

Apr 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with arginine at codon 764 of the LDLR protein (p.Ile764Arg). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and arginine. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 920005). This variant is not present in population databases (ExAC no frequency). -

Nov 05, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Ile743Arg in the mature protein) replaces isoleucine with arginine at codon 764 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.028
DANN	Benign	0.24
DEOGEN2	Benign	0.40	T;.;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.59	T;T;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.2	L;.;.;.;.;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.31	N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.65	T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T
Polyphen		0.024	B;.;.;.;.;.
Vest4		0.17
MutPred		0.50		Gain of disorder (P = 0.0066);Gain of disorder (P = 0.0066);.;.;.;Gain of disorder (P = 0.0066);
MVP		0.84
MPC		0.38
ClinPred		0.061	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.84

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: rs759440817; hg19: chr19-11234000;