19-11113559-C-T

Variant names:

• chr19-11113559-C-T
• rs764929176
• NM_000527.5:c.1383C>T

Variant summary

Our verdict is Likely benign. The variant received 0 ACMG points: 2P and 2B. BP7 PM2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1383C>T (p.Gly461=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001157 (0.01157%) in the Latino-admixed population exomes (gnomAD v2.1.1). BP4: No REVEL, splicing evaluation required: A) not on limits B) does not create GT. Variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. This variant has two supporting strength evidence codes towards Benign, enough to classify as Likely Benign, and only one moderate strength evidence code towards Pathogenic. VCEP consensus is that PM2 is not strong enough evidence to upgrade the classification of an otherwise Benign or Likely Benign variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA034080/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 4.79
• Publications: 0 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]

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

Our verdict: Likely_benign. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1383C>T	p.Gly461Gly	synonymous	Exon 10 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1383C>T	p.Gly461Gly	synonymous	Exon 10 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1260C>T	p.Gly420Gly	synonymous	Exon 9 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.1383C>T	p.Gly461Gly	synonymous	Exon 10 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1641C>T	p.Gly547Gly	synonymous	Exon 10 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1383C>T	p.Gly461Gly	synonymous	Exon 10 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250928 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461664 Hom.: 0 Cov.: 38 AF XY: 0.0000179 AC XY: 13 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000895 AC: 4 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111952

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152150 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:3

Jul 02, 2024

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.1383C>T (p.Gly461=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001157 (0.01157%) in the Latino-admixed population exomes (gnomAD v2.1.1). BP4: No REVEL, splicing evaluation required: A) not on limits B) does not create GT. Variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. This variant has two supporting strength evidence codes towards Benign, enough to classify as Likely Benign, and only one moderate strength evidence code towards Pathogenic. VCEP consensus is that PM2 is not strong enough evidence to upgrade the classification of an otherwise Benign or Likely Benign variant.

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

0/208 non-FH alleles

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Oct 24, 2023

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.

Familial hypercholesterolemia Benign:1

Aug 09, 2024

GENinCode PLC

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a synonymous (silent) variant that is not predicted to impact splicing and occurs at a nucleotide which is not conserved. Therefore this variant has been classified as Likely Benign (BP4, BP7).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.8
DANN	Benign	0.60
PhyloP100		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs764929176; hg19: chr19-11224235; COSMIC: COSV52945018; COSMIC: COSV52945018;