19-11106628-G-C

Position:

• chr19-11106628-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (v2.1.1). PP3 - REVEL = 0.77, which is above the threshold of 0.75. PP4 - Variant meets PM2 and was identified in 1 index case with Simon Broome criteria for FH (PMID:20236128) after alternative causes of cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>A (p.Arg253Gln); however, both are VUS by these LDLR guidelines (PM5 not applicable). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585115/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 0.678

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 4 ACMG points.

• 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.758G>C	p.Arg253Pro	missense_variant	5/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.758G>C	p.Arg253Pro	missense_variant	5/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 22, 2022	The NM_000527.5(LDLR):c.758G>C (p.Arg253Pro) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying evidence PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (v2.1.1). PP3 - REVEL = 0.77, which is above the threshold of 0.75. PP4 - Variant meets PM2 and was identified in 1 index case with Simon Broome criteria for FH (PMID: 20236128) after alternative causes of cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.757C>T (p.Arg253Trp); 2) NM_000527.5(LDLR):c.758G>A (p.Arg253Gln); however, both are VUS by these LDLR guidelines (PM5 not applicable). -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T;T;D;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.1	L;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Benign	0.057	T;T;T;D;T
Sift4G	Benign	0.089	T;T;T;T;T
Polyphen		0.98	D;.;.;.;.
Vest4		0.76
MutPred		0.59		Loss of catalytic residue at R253 (P = 0.0121);Loss of catalytic residue at R253 (P = 0.0121);.;.;Loss of catalytic residue at R253 (P = 0.0121);
MVP		1.0
MPC		0.96
ClinPred		0.98	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs139507589; hg19: chr19-11217304;