NM_000527.5:c.858C>T

Variant names:

• chr19-11107432-C-T
• rs140241383
• NM_000527.5:c.858C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000527.5(LDLR):​c.858C>T​(p.Ser286Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,611,206 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 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: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -1.35
• Publications: 30 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-11107432-C-T is Benign according to our data. Variant chr19-11107432-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440609.
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.

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.858C>T	p.Ser286Ser	synonymous	Exon 6 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.858C>T	p.Ser286Ser	synonymous	Exon 6 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.735C>T	p.Ser245Ser	synonymous	Exon 5 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.858C>T	p.Ser286Ser	synonymous	Exon 6 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1116C>T	p.Ser372Ser	synonymous	Exon 6 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.858C>T	p.Ser286Ser	synonymous	Exon 6 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251430 AF XY: 0.000302

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000131 AC: 191 AN: 1459086 Hom.: 1 Cov.: 32 AF XY: 0.000131 AC XY: 95 AN XY: 725866

African (AFR) AF: 0.00365 AC: 122 AN: 33400

American (AMR) AF: 0.000381 AC: 17 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39540

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1110090

Other (OTH) AF: 0.000249 AC: 15 AN: 60194

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00104 AC XY: 77 AN XY: 74348

African (AFR) AF: 0.00347 AC: 144 AN: 41512

American (AMR) AF: 0.000722 AC: 11 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000528 Hom.: 0

Bravo AF: 0.00108

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Familial hypercholesterolemia (3)
-	1	2	Hypercholesterolemia, familial, 1 (3)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.0
DANN	Benign	0.68
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

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: rs140241383; hg19: chr19-11218108;