19-11100245-C-T

Variant names:

• chr19-11100245-C-T
• rs72658855
• NM_000527.5:c.90C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000527.5(LDLR):​c.90C>T​(p.Asn30Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,462 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0089 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (19 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -1.90
• Publications: 11 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 19-11100245-C-T is Benign according to our data. Variant chr19-11100245-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 251012.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00893 (1359/152208) while in subpopulation AFR AF = 0.031 (1288/41522). AF 95% confidence interval is 0.0296. There are 18 homozygotes in GnomAd4. There are 640 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR,SD gene

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.90C>T	p.Asn30Asn	synonymous	Exon 2 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.90C>T	p.Asn30Asn	synonymous	Exon 2 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.90C>T	p.Asn30Asn	synonymous	Exon 2 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.90C>T	p.Asn30Asn	synonymous	Exon 2 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.348C>T	p.Asn116Asn	synonymous	Exon 2 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.90C>T	p.Asn30Asn	synonymous	Exon 2 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1354 AN: 152090 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00227 AC: 571 AN: 251024 AF XY: 0.00171

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000913 AC: 1334 AN: 1461254 Hom.: 19 Cov.: 31 AF XY: 0.000878 AC XY: 638 AN XY: 726890

African (AFR) AF: 0.0330 AC: 1104 AN: 33476

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52852

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111948

Other (OTH) AF: 0.00171 AC: 103 AN: 60396

GnomAD4 genome AF: 0.00893 AC: 1359 AN: 152208 Hom.: 18 Cov.: 33 AF XY: 0.00860 AC XY: 640 AN XY: 74414

African (AFR) AF: 0.0310 AC: 1288 AN: 41522

American (AMR) AF: 0.00282 AC: 43 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68006

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00349 Hom.: 18

Bravo AF: 0.00954

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Hypercholesterolemia, familial, 1 (6)
-	-	4	Familial hypercholesterolemia (4)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.1
DANN	Benign	0.74
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs72658855; hg19: chr19-11210921;