19-11113608-G-T

Position:

• chr19-11113608-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PM5

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1432G>T (p.Gly478Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5 and PP3 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), so PM2 is met.PM5 - 2 other missense variants in the same codon:(1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg)- 1 star, Conflicting interpretations of pathogenicity​: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4)- Pathogenic by these guidelines (FH VCEP training Aug 2021)(2) NM_000527.4(LDLR):c.1433G>A (p.Gly478Glu) - 0 stars, Pathogenic- Likely pathogenic by these guidelines--- 1 Pathogenic variant in the same codon, so PM5 is met.PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404085992/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 8.03

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 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1432G>T	p.Gly478Trp	missense_variant	10/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1432G>T	p.Gly478Trp	missense_variant	10/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jan 28, 2022	The NM_000527.5(LDLR):c.1432G>T (p.Gly478Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5 and PP3 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), so PM2 is met. PM5 - 2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) - 1 star, Conflicting interpretations of pathogenicity: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4) - Pathogenic by these guidelines (FH VCEP training Aug 2021) (2) NM_000527.4(LDLR):c.1433G>A (p.Gly478Glu) - 0 stars, Pathogenic - Likely pathogenic by these guidelines --- 1 Pathogenic variant in the same codon, so PM5 is met. PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met. -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2021

The p.G478W variant (also known as c.1432G>T), located in coding exon 10 of the LDLR gene, results from a G to T substitution at nucleotide position 1432. The glycine at codon 478 is replaced by tryptophan, an amino acid with highly dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). An alternate amino acid substitution at this codon, p.G478R (also known as legacy p.G457R), has been detected in multiple individuals with familial hypercholesterolemia, suggesting a hotspot at this position (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;H
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.0	D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.84
MutPred		0.87		Gain of catalytic residue at G478 (P = 0.0891);Gain of catalytic residue at G478 (P = 0.0891);.;.;.;Gain of catalytic residue at G478 (P = 0.0891);
MVP		1.0
MPC		0.88
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.96

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: rs144614838; hg19: chr19-11224284;