NM_000527.5:c.1179G>C

Variant names:

• chr19-11111632-G-C
• rs879254816
• NM_000527.5:c.1179G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000527.5(LDLR):​c.1179G>C​(p.Lys393Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K393E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0310
• Publications: 0 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 11 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 21 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 chr19-11111630-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1740990.
• 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, 0.864
• PP5: Variant 19-11111632-G-C is Pathogenic according to our data. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11111632-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 251700.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1179G>C	p.Lys393Asn	missense_variant	Exon 8 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1179G>C	p.Lys393Asn	missense_variant	Exon 8 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;.;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;M
PhyloP100		-0.031
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D
REVEL	Uncertain	0.60
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		0.59
MutPred		0.46		Loss of methylation at K393 (P = 0.0011);Loss of methylation at K393 (P = 0.0011);.;.;.;Loss of methylation at K393 (P = 0.0011);
MVP		1.0
MPC		0.84
ClinPred		0.98	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.98
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs879254816; hg19: chr19-11222308;