rs1555808091

Positions:

• chr19-11123264-GA-AG

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2231_2232delinsAG (p.Arg744Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 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: BP4 - No REVEL, splicing evaluation needed.Functional studies are not availableA) variant not on limits.B) variant is exonic and at least 50bp downstream from the canonical acceptor site and creates de novo AG site.MES scores: de novo variant = -3.1; canonical acceptor = 8.76.Ratio de novo variant/canonical acceptor =-3.1/8.76 = -0.35 -> it is below 0.8. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658658781/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 30)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:5
• Conservation: PhyloP100: -0.822

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 Uncertain_significance. Variant got -1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2231_2232delGAinsAG	p.Arg744Gln	missense_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2231_2232delGAinsAG	p.Arg744Gln	missense_variant		1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	May 27, 2022	The NM_000527.5(LDLR):c.2231_2232delinsAG (p.Arg744Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 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: BP4 - No REVEL, splicing evaluation needed. Functional studies are not available A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site and creates de novo AG site. MES scores: de novo variant = -3.1; canonical acceptor = 8.76. Ratio de novo variant/canonical acceptor =-3.1/8.76 = -0.35 -> it is below 0.8. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2024	Variant summary: LDLR c.2231_2232delinsAG (p.Arg744Gln; also known as p.Arg723Gln in publications) results in a conservative amino acid change located in the attachment sites for O-linked sugar chains (PMID: 3005267) of the encoded protein sequence. The variant allele was found at a frequency of 0.0008 in 282692 control chromosomes (including one homozygote), predominantly at a frequency of 0.0022 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. This variant has been reported in the literature in individuals affected with Familial Hypercholesterolemia or myocardial infarction (examples, Sun_1997, Thormaehlen_2015, Corral_2018). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 15823288, 9409298, 25647241, 9544745, 30270055). ClinVar contains an entry for this variant (Variation ID: 456652). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial hypercholesterolemia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2022

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555808091; hg19: chr19-11233940;