19-11089550-T-G

Variant names:

• chr19-11089550-T-G
• rs1555800701
• NM_000527.5:c.2T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_000527.5(LDLR):​c.2T>G​(p.Met1?) variant causes a start lost 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77
• Publications: 1 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 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 676 pathogenic variants. Next in-frame start position is after 264 codons. Genomic position: 11106660. Lost 0.306 part of the original CDS.
• PS1: Another start lost variant in NM_000527.5 (LDLR) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.2T>G	p.Met1?	start_lost	Exon 1 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.2T>G	p.Met1?	start_lost	Exon 1 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000558013.5	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 18	ENSP00000453346.1	P01130-5
	LDLR	ENST00000557933.5	TSL:5	c.2T>G	p.Met1?	start_lost	Exon 1 of 18	ENSP00000453557.1	H0YMD1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.00032
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.63	D
PhyloP100		1.8
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.86	P
Vest4		0.69
MutPred		0.54		Gain of disorder (P = 0.0971)
MVP		0.99
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		-0.098	Neutral
Varity_R		0.98
gMVP		0.96
Mutation Taster		=2/198	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: rs1555800701; hg19: chr19-11200226;