19-11110690-C-T

Position:

• chr19-11110690-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.979C>T (p.His327Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS_Supporting) 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).PP3 - REVEL = 0.958PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.PS4_Supporting - Variant meets PM2 and is identified in 3 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria in PMID:9259195 (Day et al., 1997), UK; 1 case with DLCN criteria>=6 in PMID:11810272 (Fouchier et al., 2001), The Netherlands). LINK:https://erepo.genome.network/evrepo/ui/classification/CA030996/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:6 B:1
• Conservation: PhyloP100: 7.66

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 Uncertain_significance. Variant got 5 ACMG points.

• PS4: 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.979C>T	p.His327Tyr	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.979C>T	p.His327Tyr	missense_variant	7/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000598 AC: 15 AN: 250950 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461596 Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47 AN XY: 727098

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: 0.000649

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:6 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:1 Benign:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR):c.979C>T (p.His327Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS_Supporting) 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). PP3 - REVEL = 0.958 PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. PS4_Supporting - Variant meets PM2 and is identified in 3 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria in PMID: 9259195 (Day et al., 1997), UK; 1 case with DLCN criteria>=6 in PMID: 11810272 (Fouchier et al., 2001), The Netherlands). -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 2 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -

Familial hypercholesterolemia Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.His327Tyr variant in LDLR has been reported in at least 4 individuals with familial hypercholesterolemia (PMID: 9259195, 11810272, 15199436, 23833242), and has been identified in 0.05% (15/30610) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747507019). This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 251583). In vitro functional studies provide some evidence that the p.His327Tyr variant may slightly impact protein function (PMID: 19224862, 19001363). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_supporting, PS3_supporting (Richards 2015). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 21, 2022	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 327 of the LDLR protein (p.His327Tyr). This variant is present in population databases (rs747507019, gnomAD 0.05%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195, 15199436, 23833242, 27765764, 33303402, 33740630). This variant is also known as p.His306Tyr. ClinVar contains an entry for this variant (Variation ID: 251583). 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 disruptive. Experimental studies have shown that this missense change affects LDLR function (PMID: 19001363, 19224862, 23675525). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 14, 2016

Variant summary: The LDLR c.979C>T (p.His327Tyr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant. This variant is present in 8/120554 control chromosomes, which does not exceed the max expected frequency for a pathogenic variant in this gene. The variant has been reported in affected inviduals in the literature, without strong evidence for causality, including co-occurrence data and co-segregation data. Two independent functional studies reveal that this variant results in a molecular gain-of-function, i.e. enhanced LDLR binding to PCSK9. This increased affinity of PCSK9 to the LDLR would in turn lead to enhanced LDLR destruction, decreased plasma LDL-C clearance, and hypercholesterolemia. However, due to the lack of strong clinical data, this variant can not be definitively classified as pathogenic. Taken together, this variant is classified as VUS-possibly pathogenic. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The p.H327Y variant (also known as c.979C>T), located in coding exon 7 of the LDLR gene, results from a C to T substitution at nucleotide position 979. The histidine at codon 327 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Day IN et al. Hum Mutat, 1997;10:116-27; Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Kusters DM et al. J Lipid Res, 2013 Sep;54:2543-9; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Rimbert A et al. Front Genet, 2021 Jan;12:809256; Arrobas Velilla T et al. Front Genet, 2022 Aug;13:971651; Diboun I et al. Front Genet, 2022 Jul;13:927504). In vitro study noted this alteration may impact protein function (Dong H et al. J Lipid Res, 2017 Feb;58:364-374). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;M
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D
REVEL	Pathogenic	0.96
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		0.90
MutPred		0.90		Loss of disorder (P = 0.0849);Loss of disorder (P = 0.0849);.;.;.;Loss of disorder (P = 0.0849);
MVP		1.0
MPC		0.80
ClinPred		0.73	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.94

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: rs747507019; hg19: chr19-11221366;