rs1555800701

Variant names:

• chr19-11089550-T-C
• rs1555800701
• NM_000527.5:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11089550-T-C
• chr19-11089550-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2T>C (p.Met1Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, and PM5 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 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PM5 - four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. 4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. LINK:https://erepo.genome.network/evrepo/ui/classification/CA404071092/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 start_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 1.77

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]

LDLR-AS1 (HGNC:54407): (LDLR antisense RNA 1) This gene represents a regulatory lncRNA that overlaps the 5' UTR and coding sequence of the LDLR (low density lipoprotein receptor) gene. This lncRNA overlaps LDLR in the antisense orientation, and has been shown to downregulate production of the low density lipoprotein receptor. [provided by RefSeq, Jul 2019]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.2T>C	p.Met1?	start_lost	Exon 1 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2T>C	p.Met1?	start_lost	Exon 1 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1

Apr 22, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.2T>C (p.Met1Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, and PM5 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 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PM5 - four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. 4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Early-onset coronary artery disease Pathogenic:1

Jul 18, 2016

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The LDLR c.2T>C (p.Met1Thr) variant involves the alteration of initiation codon, predicted to lead to absent protein. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 115758 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. According to ACMG guidelines alterations of initiation codon is very strong evidence for pathogenicity in a gene where LOF is a known mechanism of disease. In this case, considering the absence of alternate gene transcripts and the next starting codon located at 264 amino acids downstream, the variant is very likely to cause absent protein. Other variants involving the initiation codon of LDRL gene (M1L and M1V) have been reported in patients and are listed as disease mutations in HGMD. In summary, this variant meets our criteria to be classified as probably pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;.;.;.;.;.
Eigen	Benign	0.10
Eigen_PC	Benign	-0.017
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
PROVEAN	Benign	-0.82	N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.72	P;.;.;.;.;.
Vest4		0.56
MutPred		0.57		Gain of catalytic residue at M1 (P = 0.0483);Gain of catalytic residue at M1 (P = 0.0483);Gain of catalytic residue at M1 (P = 0.0483);Gain of catalytic residue at M1 (P = 0.0483);Gain of catalytic residue at M1 (P = 0.0483);Gain of catalytic residue at M1 (P = 0.0483);
MVP		0.99
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.90

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: rs1555800701; hg19: chr19-11200226;