rs1323416354

Variant names:

• chr19-11110665-C-A
• rs1323416354
• NM_000527.5:c.954C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11110665-C-A
• chr19-11110665-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000527.5(LDLR):​c.954C>A​(p.Cys318*) variant causes a stop gained 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.479
• 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11110665-C-A is Pathogenic according to our data. Variant chr19-11110665-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 523733.Status of the report is criteria_provided_single_submitter, 1 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.954C>A	p.Cys318*	stop_gained	Exon 7 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.954C>A	p.Cys318*	stop_gained	Exon 7 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.831C>A	p.Cys277*	stop_gained	Exon 6 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.954C>A	p.Cys318*	stop_gained	Exon 7 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1212C>A	p.Cys404*	stop_gained	Exon 7 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.954C>A	p.Cys318*	stop_gained	Exon 7 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1

Mar 01, 2016

Iberoamerican FH Network

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		0.48
Vest4		0.94
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	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: rs1323416354; hg19: chr19-11221341;