rs879255171

Positions:

• chr19-11123329-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP4 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2296A>G (p.Thr766Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows: PM2: PopMax MAF= 0.00001600 (0.0016%) in Remaining group exomes (gnomAD v4.1.0).BP4: REVEL=0.481. it is below 0.50, splicing evaluation required.Functional data on splicing not available.A) variant not on limits.B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT.C) there is a GT nearby.MES scores: variant cryptic = -26.75, wt cryptic = -35.70, canonical donor = 9.06.Scores are negative, splice site not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in 1 case who fulfills Simon Broome criteria for possible FH after alternative causes of high cholesterol excluded, in PMID 20236128 (Taylor et al., 2010), UK. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585815/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, single submitter U:1
• Conservation: PhyloP100: 2.14

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: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2296A>G	p.Thr766Ala	missense_variant	15/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2296A>G	p.Thr766Ala	missense_variant	15/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461812 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727200

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Uncertain	0.61	D;.;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.63	T;T;T;T;T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.39	T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.6	D;D;N;D;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.095	T;T;T;T;T;T
Sift4G	Uncertain	0.056	T;T;T;T;D;T
Polyphen		0.97	D;.;.;.;.;.
Vest4		0.15
MutPred		0.48		Loss of glycosylation at T766 (P = 0.0131);Loss of glycosylation at T766 (P = 0.0131);.;.;.;Loss of glycosylation at T766 (P = 0.0131);
MVP		1.0
MPC		0.23
ClinPred		0.86	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.80

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: rs879255171; hg19: chr19-11234005;