rs688

Variant names:

• chr19-11116926-C-T
• rs688
• NM_000527.5:c.1773C>T

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.1773C>T​(p.Asn591Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 1,613,584 control chromosomes in the GnomAD database, including 147,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10427 hom., cov: 31)
  • Exomes 𝑓: 0.43 (136666 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -4.22
• Publications: 203 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-11116926-C-T is Benign according to our data. Variant chr19-11116926-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 200917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1773C>T	p.Asn591Asn	synonymous	Exon 12 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1773C>T	p.Asn591Asn	synonymous	Exon 12 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1650C>T	p.Asn550Asn	synonymous	Exon 11 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.1773C>T	p.Asn591Asn	synonymous	Exon 12 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2031C>T	p.Asn677Asn	synonymous	Exon 12 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1773C>T	p.Asn591Asn	synonymous	Exon 12 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51230 AN: 151818 Hom.: 10439 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.362

GnomAD2 exomes AF: 0.389 AC: 97866 AN: 251472 AF XY: 0.396

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.432

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.434

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.426 AC: 622001 AN: 1461646 Hom.: 136666 Cov.: 43 AF XY: 0.425 AC XY: 309181 AN XY: 727136

African (AFR) AF: 0.0953 AC: 3192 AN: 33478

American (AMR) AF: 0.419 AC: 18718 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 11369 AN: 26136

East Asian (EAS) AF: 0.148 AC: 5861 AN: 39700

South Asian (SAS) AF: 0.393 AC: 33938 AN: 86252

European-Finnish (FIN) AF: 0.472 AC: 25193 AN: 53410

Middle Eastern (MID) AF: 0.448 AC: 2581 AN: 5758

European-Non Finnish (NFE) AF: 0.447 AC: 496547 AN: 1111798

Other (OTH) AF: 0.407 AC: 24602 AN: 60390

GnomAD4 genome AF: 0.337 AC: 51210 AN: 151938 Hom.: 10427 Cov.: 31 AF XY: 0.341 AC XY: 25314 AN XY: 74240

African (AFR) AF: 0.107 AC: 4420 AN: 41494

American (AMR) AF: 0.426 AC: 6484 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1452 AN: 3468

East Asian (EAS) AF: 0.172 AC: 890 AN: 5160

South Asian (SAS) AF: 0.393 AC: 1894 AN: 4820

European-Finnish (FIN) AF: 0.493 AC: 5197 AN: 10538

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29676 AN: 67940

Other (OTH) AF: 0.360 AC: 755 AN: 2098

Alfa AF: 0.408 Hom.: 36690

Bravo AF: 0.321

Asia WGS AF: 0.266 AC: 923 AN: 3478

EpiCase AF: 0.438

EpiControl AF: 0.442

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	Hypercholesterolemia, familial, 1 (9)
-	-	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	-0.74
CADD	Benign	0.092
DANN	Benign	0.70
PhyloP100		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs688; hg19: chr19-11227602; COSMIC: COSV52942945; COSMIC: COSV52942945;