19-11089549-A-G

Variant names:

• chr19-11089549-A-G
• rs879254382
• NM_000527.5:c.1A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Moderate PM5 PM2 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1A>G (p.Met1Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PM5, PS4_Supporting, 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 - variant is absent from gnomAD (v2.1.1).PVS1_Moderate – variant is predicted to affect the initiation codon.PS4_Supporting – variant meets PM2 and is identified in 3 unrelated index cases who fulfill clinical criteria for FH (3 cases with SB criteria from PMID:11462246).PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.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_000527.4(LDLR):c.2T>C (p.Met1Thr) - 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/CA10584719/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:5
• Conservation: PhyloP100: 2.21
• Publications: 118 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]

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.
• PP4: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000558013.5	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 18	ENSP00000453346.1	P01130-5
	LDLR	ENST00000557933.5	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 1 of 18	ENSP00000453557.1	H0YMD1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Hypercholesterolemia, familial, 1 (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.022
Eigen_PC	Benign	-0.082
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.58	D
PhyloP100		2.2
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.32	B
Vest4		0.68
MutPred		0.56		Loss of disorder (P = 0.1071)
MVP		0.99
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.88
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879254382; hg19: chr19-11200225;