rs5926

Variant names:

• chr19-11120166-C-T
• rs5926
• NM_000527.5:c.1920C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-11120166-C-T
• chr19-11120166-C-G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP7 BA1 BS3_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1920C>T (p.Asn640=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BP4, BP7, BS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:BA1: FAF=0.03838 in Ashkenazi Jewish population in gnomAD (gnomAD 2.1.1).BP4: No REVEL, splicing evaluation required. A) not in limit. B) does not create AG or GT. C) there is a GT nearby. Var cryptic score/Wt cryptic score=0.69, it is not above 1.1, and Var cryptic score/Wt score= -0.80, it is not above 0.9. Variant is not predicted to alter splicing.BP7: Variant is synonymous and meets BP4.BS3_Supporting: Level 3 assay with heterozygous patients’ lymphocytes, RNA assays shown normal LDLR transcripts, reported by Medeiros et al, 2016, from Instituto Nacional de Saude Doutor Ricardo Jorge, Lisbon, Portugal, PMID 26020417. Functional data is consistent with no damaging effect.PP4, PS4 not met: Variant did not meet PM2.PP1 not met: There are 2 relatives without the variant had LDL-C <50th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BS4 not met: There are 2 relatives without the variant had LDL-C >75th percentile in 1 family, however the index case did not meet Simon Broome criteria for FH diagnosis, and there is no instance where an unaffected family member carries the variant, reported in VCI from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.BP2 not met: Variant identified in an index case with heterozygous FH phenotype and an unspecified LDLR variant with unknown pathogenicity and phase, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. LINK:https://erepo.genome.network/evrepo/ui/classification/CA037448/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (27 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:3 B:19
• Conservation: PhyloP100: -1.67
• Publications: 15 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 -11 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1920C>T	p.Asn640Asn	synonymous	Exon 13 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1920C>T	p.Asn640Asn	synonymous	Exon 13 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1797C>T	p.Asn599Asn	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.1920C>T	p.Asn640Asn	synonymous	Exon 13 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.2178C>T	p.Asn726Asn	synonymous	Exon 13 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1920C>T	p.Asn640Asn	synonymous	Exon 13 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 484 AN: 152166 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00436 AC: 1096 AN: 251492 AF XY: 0.00448

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00368

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00303 AC: 4424 AN: 1461720 Hom.: 27 Cov.: 33 AF XY: 0.00313 AC XY: 2279 AN XY: 727182

African (AFR) AF: 0.00167 AC: 56 AN: 33480

American (AMR) AF: 0.00360 AC: 161 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0355 AC: 929 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86256

European-Finnish (FIN) AF: 0.00399 AC: 213 AN: 53420

Middle Eastern (MID) AF: 0.0265 AC: 153 AN: 5768

European-Non Finnish (NFE) AF: 0.00222 AC: 2472 AN: 1111852

Other (OTH) AF: 0.00603 AC: 364 AN: 60390

GnomAD4 genome AF: 0.00318 AC: 484 AN: 152284 Hom.: 5 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74468

African (AFR) AF: 0.000601 AC: 25 AN: 41570

American (AMR) AF: 0.00282 AC: 43 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3472

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

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00326 AC: 222 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00400 Hom.: 6

Bravo AF: 0.00301

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00450

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	7	Hypercholesterolemia, familial, 1 (10)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	3	Familial hypercholesterolemia (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.34
DANN	Benign	0.91
PhyloP100		-1.7
Mutation Taster		=98/2	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: rs5926; hg19: chr19-11230842;