rs879254386

Variant names:

• chr19-11089576-T-A
• rs879254386
• NM_000527.5:c.28T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11089576-T-A
• chr19-11089576-T-C
• chr19-11089576-T-G

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_000527.5(LDLR):​c.28T>A​(p.Trp10Arg) 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 Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.81
• 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-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS1: Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 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
• 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, 0.819
• PP5: Variant 19-11089576-T-A is Pathogenic according to our data. Variant chr19-11089576-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 250975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.28T>A	p.Trp10Arg	missense_variant	Exon 1 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.28T>A	p.Trp10Arg	missense_variant	Exon 1 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

- -

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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D;.;.;.;.;.
Eigen	Benign	0.018
Eigen_PC	Benign	-0.0087
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.65	T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.6	L;.;L;L;L;L
PhyloP100		2.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.98	N;N;N;N;N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Benign	0.31	T;D;D;T;D;T
Polyphen		0.84	P;.;.;.;.;.
Vest4		0.53
MutPred		0.69		Loss of catalytic residue at L8 (P = 0.0013);Loss of catalytic residue at L8 (P = 0.0013);Loss of catalytic residue at L8 (P = 0.0013);Loss of catalytic residue at L8 (P = 0.0013);Loss of catalytic residue at L8 (P = 0.0013);Loss of catalytic residue at L8 (P = 0.0013);
MVP		1.0
MPC		0.86
ClinPred		0.94	D
GERP RS		3.7
PromoterAI		0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.46
gMVP		0.89
Mutation Taster		=1/99	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: rs879254386; hg19: chr19-11200252;