19-11107511-T-C

Position:

• chr19-11107511-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3 PP4 PS4_Supporting PM1

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.937T>C (p.Cys313Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM1, PP4, PS4_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=0.978.PM1: Variant meets PM2 and is one of the cysteine residues listed involving disulfide bone formation.PP4: Variant meets PM2 and is identified in ˃1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded.PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases reported in PubMed: one case fulfil Simon Broome criteria for definite or possible FH in PMID 22881376, reported by Usifo et al, 2012, from British Heart Foundation Laboratories, University College London, UK; one case fulfil DLCN ≥6 in PMID 19318025 reported by Alonso et al, 2009, from Lipid Clinic, Fundacion Jimenez Diaz, Spain. PS3 not met: Functional data is not available.PM5 not met: Three other missense variants at same codon: NM_000527.5 (LDLR):c.937T>G (p.Cys313Gly), ClinVarID 251538, is classified as Uncertain significance; NM_000527.5 (LDLR):c.939C>G (p.Cys313Trp), ClinVarID 251540, is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.938G>A (p.Cys313Tyr), ClinVarID 226339, is classified as Likely Pathogenic by these guidelines, therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585207/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 U:1
• Conservation: PhyloP100: 7.92

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 7 ACMG points.

• PS4: 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.
• 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.937T>C	p.Cys313Arg	missense_variant	6/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.937T>C	p.Cys313Arg	missense_variant	6/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5 (LDLR):c.937T>C (p.Cys313Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM1, PP4, PS4_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=0.978. PM1: Variant meets PM2 and is one of the cysteine residues listed involving disulfide bone formation. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases reported in PubMed: one case fulfil Simon Broome criteria for definite or possible FH in PMID 22881376, reported by Usifo et al, 2012, from British Heart Foundation Laboratories, University College London, UK; one case fulfil DLCN >=6 in PMID 19318025 reported by Alonso et al, 2009, from Lipid Clinic, Fundacion Jimenez Diaz, Spain. PS3 not met: Functional data is not available. PM5 not met: Three other missense variants at same codon: NM_000527.5 (LDLR):c.937T>G (p.Cys313Gly), ClinVarID 251538, is classified as Uncertain significance; NM_000527.5 (LDLR):c.939C>G (p.Cys313Trp), ClinVarID 251540, is classified as Likely Pathogenic; NM_000527.5 (LDLR):c.938G>A (p.Cys313Tyr), ClinVarID 226339, is classified as Likely Pathogenic by these guidelines, therefore PM5 is not met. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;.;.;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T;T;T;T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.;H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-10	D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.90
MutPred		0.94		Gain of disorder (P = 0.0373);Gain of disorder (P = 0.0373);.;.;.;Gain of disorder (P = 0.0373);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

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: rs879254728; hg19: chr19-11218187;