NM_000527.5:c.313+1G>C

Variant names:

• chr19-11102787-G-C
• rs112029328
• NM_000527.5:c.313+1G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000527.5(LDLR):​c.313+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene LDLR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LDLR NM_000527.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:1
• Conservation: PhyloP100: 8.10
• Publications: 44 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04761905 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of -50, new splice context is: gagGTgcga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11102787-G-C is Pathogenic according to our data. Variant chr19-11102787-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228358.

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.313+1G>C		splice_donor intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001406861.1		c.572G>C	p.Arg191Pro	missense	Exon 3 of 3	NP_001393790.1
	LDLR	NM_001195798.2		c.313+1G>C		splice_donor intron	N/A	NP_001182727.1	P01130-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.313+1G>C		splice_donor intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.571+1G>C		splice_donor intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.313+1G>C		splice_donor intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251424 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460880 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726744

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111370

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	-	-	Hypercholesterolemia, familial, 1 (7)
4	1	-	Familial hypercholesterolemia (5)
3	-	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Homozygous familial hypercholesterolemia (1)
1	-	-	LDLR-related disorder (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	0.97
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		8.1
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112029328; hg19: chr19-11213463;