rs750649426

chr19-11111629-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):c.1176C>A(p.Cys392Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. C392C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 4.02

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11111629-C-A is Pathogenic according to our data. Variant chr19-11111629-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 251699.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11111629-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1176C>A	p.Cys392Ter	stop_gained	8/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1176C>A	p.Cys392Ter	stop_gained	8/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250606 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135616

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / previously described in association with FH -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/200 non-FH alleles; 0/200 Brazilian (european ancestry) normolipidemic individuals; 0/200 normal chromosomes -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 28, 2022	The NM_000527.5(LDLR):c.1176C>A (p.Cys392Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PM2, PM3, PS4_Moderate 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: PVS1 - variant is nonsense, causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830), so PVS1 is met. PP1_strong - variant segregates with FH phenotype in: - 7 informative meiosis from 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 4 relatives positive for variant with LDL-C >75th percentile, and 3 relatives negative for variant with LDL-C <50th percentile. - 1 informative meiosis from 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 1 relative positive for variant with LDL-C >75th percentile. - 11 informative meiosis from 1 family from PMID: 8831933 (Langenhoven et al. 1996): 11 relatives are positive for the variant and have LDL-C >75th percentile (9 have >5.0mmol, 2 have 4.6 and 4.3mmol) Segregation was observed in 19 informative meiosis from 3 families, so PP1_Strong is met. PM2 - PopMax MAF = 0.00003267 (0.003%) in South asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM3 - variant meets PM2 and was identified in 1 index case who also carries NM_000527.5(LDLR):c.1A>T (p.Met1Leu), confirmed in trans, who has LDL 17.3mmol/L from PMID: 8831933 (Langenhoven et al. 1996 Aug 23;125(1):111-9. --- 2nd variant is classified as Pathogenic with these guidelines, so PM3 is met. PS4_moderate - variant meets PM2 and was identified in: - 1 index case who fulfills Simon-Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 1 index case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 4 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada; - 1 Index case (iii-4) with DLCN at least 8 (LDL-C 17.3mmol at 4yo with tendon xanthoma) from PMID: 8831933 (Langenhoven et al. 1996), South Africa; - 1 index case with heterozygous FH per MEDPED criteria from PMID: 11933210 (Salazar et al. 2002), Brazil; - at least 1 index case with definite FH ("definite heterozygous FH by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 11810272 (Fouchier et al. 2001), The Netherlands. 9 unrelated cases, so PS4_Moderate is met. PP4 - variant meets PM2 and was identified in 9 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is met. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 11, 2019

The p.Cys392X variant (also described as p.Cys371 in the literature) in LDLR has been reported in the heterozygous state at least 8 individuals with familial hypercholesterolemia (FH) and in the compound heterozygous state in one individual with another pathogenic LDLR variant, and segregated with disease in 11 affected relatives from 1 family (Langenhoven 1996, Fouchier 2001, Salazar 2002, Leren 2004, Mozas 2004, Medieros 2010). This variant has also been reported by other clinical labs in ClinVar (Variation ID: 251699) and has been identified in 0.003% (1/30612) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. This nonsense variant leads to a premature termination codon at position 392, which is predicted to lead to a truncated or absent protein. In vitro functional studies also support an impact on protein function (Langenhoven 1996). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PP1_Moderate, PM2, PS4_Moderate, PS3_Supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32041611, 8831933, 33303402, 33740630, 35339733, 15241806, 34037665, 21382890, 11933210, 25461735, 20828696, 17094996) -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251699). This variant is also known as Cys371*. This premature translational stop signal has been observed in individuals with heterozygous and homozygous familial hypercholesterolemia (PMID: 8831933, 11933210, 20828696, 21382890, 25461735). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Cys392*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.94
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs750649426; hg19: chr19-11222305;