19-11102765-G-C

Variant names:

• chr19-11102765-G-C
• rs750474121
• NM_000527.5:c.292G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.292G>C (p.Gly98Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP4: Variant meets PM2 and is identified in 1 case with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584830/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 4.20
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.292G>C	p.Gly98Arg	missense	Exon 3 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.292G>C	p.Gly98Arg	missense	Exon 3 of 18	NP_001182727.1
	LDLR	NM_001195800.2		c.292G>C	p.Gly98Arg	missense	Exon 3 of 16	NP_001182729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.292G>C	p.Gly98Arg	missense	Exon 3 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.550G>C	p.Gly184Arg	missense	Exon 3 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.292G>C	p.Gly98Arg	missense	Exon 3 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:2

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

0/208 non-FH alleles

Feb 23, 2024

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.292G>C (p.Gly98Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 case with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded.

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.2
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.67	P
Vest4		0.45
MutPred		0.74		Loss of catalytic residue at D96 (P = 0.2137)
MVP		1.0
MPC		0.55
ClinPred		0.98	D
GERP RS		3.5
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.56
gMVP		0.96
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs750474121; hg19: chr19-11213441;