19-11100236-C-T

Position:

• chr19-11100236-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000527.5(LDLR):​c.81C>T​(p.Cys27=) 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:17
• Conservation: PhyloP100: -0.152

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 251010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11100236-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.81C>T	p.Cys27=	synonymous_variant	2/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.81C>T	p.Cys27=	synonymous_variant	2/18	1	NM_000527.5	ENSP00000454071	P3

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

GnomAD3 exomes AF: 0.0886 AC: 22217 AN: 250746 Hom.: 1184 AF XY: 0.0905 AC XY: 12273 AN XY: 135548

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 SAS exome AF: 0.0715

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

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.0954

Gnomad4 EAS exome AF: 0.00594

Gnomad4 SAS exome AF: 0.0716

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.102

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

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.0877

Gnomad4 ASJ AF: 0.0925

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.0657

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.0915

Alfa AF: 0.108 Hom.: 2197

Bravo AF: 0.0856

Asia WGS AF: 0.0430 AC: 151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:8

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	3 Hmz + 28 Htz / 95 non-FH individuals; MAF = 13,4% in 86 Spanish healthy individuals -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Feb 08, 2019	Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as benign. -
Benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial hypercholesterolemia Benign:3

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 22, 2022	- -

Smith-Lemli-Opitz syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.6
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228671; hg19: chr19-11210912;