rs5925

Variant names:

• chr19-11120205-T-C
• rs5925
• NM_000527.5:c.1959T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000527.5(LDLR):​c.1959T>C​(p.Val653Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,613,320 control chromosomes in the GnomAD database, including 154,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11896 hom., cov: 32)
  • Exomes 𝑓: 0.44 (142207 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.228
• Publications: 104 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-11120205-T-C is Benign according to our data. Variant chr19-11120205-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.228 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

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.1959T>C	p.Val653Val	synonymous	Exon 13 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1959T>C	p.Val653Val	synonymous	Exon 13 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1836T>C	p.Val612Val	synonymous	Exon 12 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.1959T>C	p.Val653Val	synonymous	Exon 13 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2217T>C	p.Val739Val	synonymous	Exon 13 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1959T>C	p.Val653Val	synonymous	Exon 13 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57193 AN: 151854 Hom.: 11898 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.395

GnomAD2 exomes AF: 0.421 AC: 105927 AN: 251320 AF XY: 0.424

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.222

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.436 AC: 637807 AN: 1461348 Hom.: 142207 Cov.: 48 AF XY: 0.436 AC XY: 317056 AN XY: 727030

African (AFR) AF: 0.190 AC: 6357 AN: 33474

American (AMR) AF: 0.526 AC: 23540 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 11380 AN: 26128

East Asian (EAS) AF: 0.194 AC: 7697 AN: 39700

South Asian (SAS) AF: 0.434 AC: 37404 AN: 86252

European-Finnish (FIN) AF: 0.476 AC: 25416 AN: 53412

Middle Eastern (MID) AF: 0.456 AC: 2633 AN: 5768

European-Non Finnish (NFE) AF: 0.448 AC: 497842 AN: 1111522

Other (OTH) AF: 0.423 AC: 25538 AN: 60376

GnomAD4 genome AF: 0.376 AC: 57217 AN: 151972 Hom.: 11896 Cov.: 32 AF XY: 0.381 AC XY: 28269 AN XY: 74266

African (AFR) AF: 0.204 AC: 8444 AN: 41474

American (AMR) AF: 0.507 AC: 7720 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1458 AN: 3470

East Asian (EAS) AF: 0.216 AC: 1116 AN: 5160

South Asian (SAS) AF: 0.435 AC: 2097 AN: 4820

European-Finnish (FIN) AF: 0.497 AC: 5251 AN: 10558

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29861 AN: 67936

Other (OTH) AF: 0.392 AC: 828 AN: 2110

Alfa AF: 0.408 Hom.: 28103

Bravo AF: 0.368

Asia WGS AF: 0.338 AC: 1175 AN: 3478

EpiCase AF: 0.440

EpiControl AF: 0.444

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Hypercholesterolemia, familial, 1 (7)
-	-	6	not specified (6)
-	-	4	Familial hypercholesterolemia (4)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.8
DANN	Benign	0.66
PhyloP100		-0.23
Mutation Taster		=97/3	polymorphism (auto)

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: rs5925; hg19: chr19-11230881; COSMIC: COSV52943342;