chr19-11100236-C-T

Variant names:

• chr19-11100236-C-T
• rs2228671
• NM_000527.5:c.81C>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.81C>T​(p.Cys27Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,612,538 control chromosomes in the GnomAD database, including 10,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (714 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9706 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.152
• Publications: 159 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=-0.66).
• BP6: Variant 19-11100236-C-T is Benign according to our data. Variant chr19-11100236-C-T is described in ClinVar as Benign. ClinVar VariationId is 251010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.152 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 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.81C>T	p.Cys27Cys	synonymous	Exon 2 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.81C>T	p.Cys27Cys	synonymous	Exon 2 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.81C>T	p.Cys27Cys	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.81C>T	p.Cys27Cys	synonymous	Exon 2 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.339C>T	p.Cys113Cys	synonymous	Exon 2 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.81C>T	p.Cys27Cys	synonymous	Exon 2 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13353 AN: 151898 Hom.: 715 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0669

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0920

GnomAD2 exomes AF: 0.0886 AC: 22217 AN: 250746 AF XY: 0.0905

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.0651

Gnomad ASJ exome AF: 0.0951

Gnomad EAS exome AF: 0.00957

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.0994

GnomAD4 exome AF: 0.111 AC: 162567 AN: 1460522 Hom.: 9706 Cov.: 32 AF XY: 0.110 AC XY: 79561 AN XY: 726564

African (AFR) AF: 0.0355 AC: 1190 AN: 33478

American (AMR) AF: 0.0669 AC: 2992 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 2493 AN: 26126

East Asian (EAS) AF: 0.00594 AC: 236 AN: 39698

South Asian (SAS) AF: 0.0716 AC: 6179 AN: 86254

European-Finnish (FIN) AF: 0.105 AC: 5512 AN: 52480

Middle Eastern (MID) AF: 0.0992 AC: 572 AN: 5768

European-Non Finnish (NFE) AF: 0.123 AC: 137211 AN: 1111620

Other (OTH) AF: 0.102 AC: 6182 AN: 60374

GnomAD4 genome AF: 0.0878 AC: 13345 AN: 152016 Hom.: 714 Cov.: 32 AF XY: 0.0878 AC XY: 6525 AN XY: 74294

African (AFR) AF: 0.0395 AC: 1641 AN: 41494

American (AMR) AF: 0.0877 AC: 1339 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 321 AN: 3470

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5178

South Asian (SAS) AF: 0.0657 AC: 315 AN: 4794

European-Finnish (FIN) AF: 0.117 AC: 1234 AN: 10552

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8126 AN: 67948

Other (OTH) AF: 0.0915 AC: 193 AN: 2110

Alfa AF: 0.105 Hom.: 4114

Bravo AF: 0.0856

Asia WGS AF: 0.0430 AC: 151 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	Hypercholesterolemia, familial, 1 (8)
-	-	4	not specified (4)
-	-	3	Familial hypercholesterolemia (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	Smith-Lemli-Opitz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.6
DANN	Benign	0.63
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228671; hg19: chr19-11210912;