chr19-11105346-C-T

Variant names:

• chr19-11105346-C-T
• rs879254524
• NM_000527.5:c.440C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_Supporting PM2 PM1 PP3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, 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: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584919/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 5.71

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.440C>T	p.Thr147Ile	missense_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.440C>T	p.Thr147Ile	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Apr 28, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, 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: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity ---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met. -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 06, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2, PS4_Moderate, PP3 -

May 24, 2021

Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reduced activity in functional assays. -

not provided Pathogenic:1

Dec 21, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Sep 13, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T147I variant (also known as c.440C>T), located in coding exon 4 of the LDLR gene, results from a C to T substitution at nucleotide position 440. The threonine at codon 147 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in two individuals from a familial hypercholesterolemia cohort and shown to reduce LDLR activity to 56% of normal levels in vivo (Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. 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. -

Familial hypercholesterolemia Pathogenic:1

Feb 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Thr126Ile in the mature protein) replaces threonine with isoleucine at codon 147 in the LDLR type A repeat 4 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a partial loss of LDLR function (PMID: 21865347). Threonine at this position is located in a functionally important region, and missense variants at this position are expected to interrupt glycosylation of linker regions in LDLR (PMID: 24798328). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 21865347, 34297352; Color internal data; communication with an external laboratory; ClinVar SCV002633357.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;M
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.70
MutPred		0.55		Loss of glycosylation at T147 (P = 0.0164);Loss of glycosylation at T147 (P = 0.0164);.;Loss of glycosylation at T147 (P = 0.0164);
MVP		1.0
MPC		0.80
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.62
gMVP		0.86

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: rs879254524; hg19: chr19-11216022;