19-11089576-T-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000527.5(LDLR):​c.28T>G​(p.Trp10Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,376 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W10R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81
• 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-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: Likely_pathogenic. The variant received 7 ACMG points.

• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11089576-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 250976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.

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.28T>G	p.Trp10Gly	missense	Exon 1 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.28T>G	p.Trp10Gly	missense	Exon 1 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.28T>G	p.Trp10Gly	missense	Exon 1 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.28T>G	p.Trp10Gly	missense	Exon 1 of 18	ENSP00000454071.1
	LDLR	ENST00000558013.5	TSL:1	c.28T>G	p.Trp10Gly	missense	Exon 1 of 18	ENSP00000453346.1
	LDLR	ENST00000557933.5	TSL:5	c.28T>G	p.Trp10Gly	missense	Exon 1 of 18	ENSP00000453557.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460376 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726474

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5070

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		0.59	P
Vest4		0.43
MutPred		0.68		Loss of catalytic residue at L8 (P = 0.0053)
MVP		1.0
MPC		0.64
ClinPred		0.83	D
GERP RS		3.7
PromoterAI		-0.048	Neutral
Varity_R		0.37
gMVP		0.88
Mutation Taster		=21/79	disease causing

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;