rs764104777

Variant names:

• chr19-11116953-G-C
• rs764104777
• NM_000527.5:c.1800G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11116953-G-C
• chr19-11116953-G-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1800G>C (p.Glu600Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specifications version 1.2) on 4 May 2023. The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA404089805/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 reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 0.0120

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1800G>C	p.Glu600Asp	missense_variant	Exon 12 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1800G>C	p.Glu600Asp	missense_variant	Exon 12 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 04, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.1800G>C (p.Glu600Asp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specifications version 1.2) on 4 May 2023. The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). -

Familial hypercholesterolemia Uncertain:1

Apr 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 18096825). ClinVar contains an entry for this variant (Variation ID: 431535). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 600 of the LDLR protein (p.Glu600Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;.;.;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T;T;T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T
MetaSVM	Uncertain	-0.00060	T
MutationAssessor	Benign	0.61	N;.;.;.;.;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.20	T;T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T;T
Polyphen		0.037	B;.;.;.;.;.
Vest4		0.33
MutPred		0.72		Loss of ubiquitination at K603 (P = 0.0992);Loss of ubiquitination at K603 (P = 0.0992);.;.;.;Loss of ubiquitination at K603 (P = 0.0992);
MVP		1.0
MPC		0.26
ClinPred		0.29	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs764104777; hg19: chr19-11227629;