19-11110714-G-T

Position:

• chr19-11110714-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3 PP4 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PS3_moderate - Level 2 FS: Hu et al. 2021 (PMID:34970301): Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake.---- part of the LDLR cycle (uptake) is less than 70% activity of wild-type, so PS3_Moderate is met.PP3 - REVEL = 0.889. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 1 index case from Hu et al. 2021 (PMID:34970301) with 5.5mmol/L LDL under no medication, and family history of hypercholesterolemia, so Simon-Broome possible is met; so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404082719/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.68

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]

LDLR (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1003G>T	p.Gly335Cys	missense_variant	7/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1003G>T	p.Gly335Cys	missense_variant	7/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2023	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 335 of the LDLR protein (p.Gly335Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 33740630, 34970301; Invitae). ClinVar contains an entry for this variant (Variation ID: 1395739). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 34970301). This variant disrupts the p.Gly335 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1073562, 1301956, 11668627, 15556094, 27765764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2024	Variant summary: LDLR c.1003G>T (p.Gly335Cys) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251016 control chromosomes. c.1003G>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia as a heterozygous and compound heterozygous genotype (e.g. Leren_2021, Hu_2021, Du_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing reduced LDL uptake of (43% of WT) in vitro (e.g. Hu_2021). The following publications have been ascertained in the context of this evaluation (PMID: 36325061, 34970301, 33740630). ClinVar contains an entry for this variant (Variation ID: 1395739). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hypercholesterolemia, familial, 1 Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Apr 28, 2023

The NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PS3_moderate - Level 2 FS: Hu et al. 2021 (PMID: 34970301): Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake. ---- part of the LDLR cycle (uptake) is less than 70% activity of wild-type, so PS3_Moderate is met. PP3 - REVEL = 0.889. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case from Hu et al. 2021 (PMID: 34970301) with 5.5mmol/L LDL under no medication, and family history of hypercholesterolemia, so Simon-Broome possible is met; so PP4 is met. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;H
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-8.6	D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.89
MutPred		0.83		Loss of ubiquitination at K333 (P = 0.0907);Loss of ubiquitination at K333 (P = 0.0907);.;.;.;Loss of ubiquitination at K333 (P = 0.0907);
MVP		1.0
MPC		0.83
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11221390;