NM_000527.5:c.1194C>T

Variant names:

• chr19-11113285-C-T
• rs13306498
• NM_000527.5:c.1194C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP7 BS1 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.1194C>T (p.Ile398=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows:BS1 - FAF = 0.00448 (0.448%) in East Asian exomes (gnomAD v2.1.1).BP4 - No REVEL, splicing evaluation required.Functional data on splicing not available.Variant is not located within the limits of canonical splicing sitesVariant is exonic and at least 50bp upstream from canonical donor site but does not creates AGThere is no AG NearbyVariant is not predicted to alter splicing.BP7 - Variant is synonymous and meets BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA033001/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel P:1 B:16
• Conservation: PhyloP100: -1.08

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]

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_benign. Variant got -6 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.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1194C>T	p.Ile398Ile	synonymous_variant	Exon 9 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1194C>T	p.Ile398Ile	synonymous_variant	Exon 9 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 235 AN: 152080 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00174 AC: 437 AN: 250716 Hom.: 4 AF XY: 0.00167 AC XY: 227 AN XY: 135748

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00533

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00119 AC: 1745 AN: 1460576 Hom.: 17 Cov.: 33 AF XY: 0.00117 AC XY: 849 AN XY: 726594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0174

Gnomad4 SAS exome AF: 0.000615

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.000326

Gnomad4 OTH exome AF: 0.000945

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152198 Hom.: 1 Cov.: 29 AF XY: 0.00206 AC XY: 153 AN XY: 74398

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000560 Hom.: 0

Bravo AF: 0.000623

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Benign:6

May 18, 2021

Pars Genome Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2016

Cardiovascular Biomarker Research Laboratory, Mayo Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

MAF =<0.3% -

Aug 28, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Aug 29, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR): c.1194C>T (p.Ile398=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying evidence code BS1, BP4 and BP7 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: BS1 - FAF = 0.00448 (0.448%) in East Asian exomes (gnomAD v2.1.1). BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. Variant is not located within the limits of canonical splicing sites Variant is exonic and at least 50bp upstream from canonical donor site but does not creates AG There is no AG Nearby Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4 -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jul 17, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

not provided Benign:4

Jan 09, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17347910, 32719484) -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: BP4, BP7, BS1 -

not specified Benign:2

Jun 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1194C>T alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0017 in 250716 control chromosomes, predominantly at a frequency of 0.0053 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013). c.1194C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Al-Khateeb_2011, Komarova_2013) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Co-occurrences with other pathogenic variant(s) have been reported (LDLR, p. Ser65Glyfs*64; LDLR, p. Trp562Cysfs*5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21418584, 24373485). ClinVar contains an entry for this variant (Variation ID: 224620). Based on the evidence outlined above, the variant was classified as benign. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial hypercholesterolemia Benign:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2024

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1 -

Autosomal dominant familial hypercholesterolemia Benign:1

May 30, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

May 13, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	-0.51
CADD	Benign	6.4
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13306498; hg19: chr19-11223961; COSMIC: COSV52944512; COSMIC: COSV52944512;