rs730882078

Positions:

• chr19-11102714-C-A
• chr19-11102714-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.241C>A (p.Arg81Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP4 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:PM2 - This variant is absent from gnomAD (v2.1.1).PP4 - Variant meet PM2. PMID:21382890 (Graaf et al., 2011) - 1 case with LDL-C level >95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, ie, at least 1 biological parent on treatment for hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease. Alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584803/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 4.83

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 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.241C>A	p.Arg81Ser	missense_variant	3/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.241C>A	p.Arg81Ser	missense_variant	3/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	The NM_000527.5(LDLR): c.241C>A (p.Arg81Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP4 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: PM2 - This variant is absent from gnomAD (v2.1.1). PP4 - Variant meet PM2. PMID: 21382890 (Graaf et al., 2011) - 1 case with LDL-C level >95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, ie, at least 1 biological parent on treatment for hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease. Alternative causes of high cholesterol were excluded. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.4	L;.;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.2	D;D;N;N;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0050	D;D;T;D;D
Sift4G	Benign	0.084	T;T;T;T;T
Polyphen		0.99	D;.;.;.;.
Vest4		0.57
MutPred		0.74		Loss of MoRF binding (P = 0.0522);Loss of MoRF binding (P = 0.0522);Loss of MoRF binding (P = 0.0522);Loss of MoRF binding (P = 0.0522);Loss of MoRF binding (P = 0.0522);
MVP		1.0
MPC		0.81
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730882078; hg19: chr19-11213390;