19-11120370-G-A

Variant names:

• chr19-11120370-G-A
• rs879255102
• NM_000527.5:c.1988G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.1988G>A​(p.Gly663Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G663A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense, splice_region
• Scores: Splicing: ADA: 0.4976
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.37
• Publications: 3 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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11120370-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 430791.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 19-11120370-G-A is Pathogenic according to our data. Variant chr19-11120370-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 252155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1988G>A	p.Gly663Glu	missense splice_region	Exon 14 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1988G>A	p.Gly663Glu	missense splice_region	Exon 14 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1865G>A	p.Gly622Glu	missense splice_region	Exon 13 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1988G>A	p.Gly663Glu	missense splice_region	Exon 14 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2246G>A	p.Gly749Glu	missense splice_region	Exon 14 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1988G>A	p.Gly663Glu	missense splice_region	Exon 14 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

not provided Pathogenic:1

Mar 04, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Also known as p.G642E; This variant is associated with the following publications: (PMID: 21868016, 11668640, 37409534, 11600564)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.039	D
Polyphen		0.99	D
Vest4		0.53
MutPred		0.84		Loss of catalytic residue at V664 (P = 0.1231)
MVP		1.0
MPC		0.48
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.61
gMVP		0.96
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.68		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255102; hg19: chr19-11231046;