19-11100340-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PM1 PM2 PM5 BP4 BP6_Strong

The NM_000527.5(LDLR):c.185C>T(p.Thr62Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000769 in 1,613,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T62R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:12 B:2 O:1
• Conservation: PhyloP100: 1.42

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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11100340-C-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 375775.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40948337).
• BP6: Variant 19-11100340-C-T is Benign according to our data. Variant chr19-11100340-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 161273.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Uncertain_significance=10, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.185C>T	p.Thr62Met	missense_variant	2/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.185C>T	p.Thr62Met	missense_variant	2/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 250804 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000712 AC: 104 AN: 1461216 Hom.: 0 Cov.: 31 AF XY: 0.0000784 AC XY: 57 AN XY: 726888

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74396

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000906 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:12 Benign:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:7 Benign:1

Likely benign, 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 / Software predictions: Damaging -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 23, 2021	The NM_000527.5(LDLR):c.185C>T (p.Thr62Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - variant segregates with FH phenotype in 3 informative meiosis in 2 families from different labs (Laboratory of Genetics and Molecular Cardiology and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 15, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	May 08, 2015	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	literature only;research	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Familial hypercholesterolemia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 62 of the LDLR protein (p.Thr62Met). This variant is present in population databases (rs376207800, gnomAD 0.02%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 16250003, 19446849, 19717150, 25606447, 26892515, 33303402). This variant is also known as p.Thr41Met. ClinVar contains an entry for this variant (Variation ID: 161273). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 11, 2022	- -

not provided Uncertain:1 Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 07, 2023	The p.Thr62Met (also reported as p.Thr41Met) variant in LDLR has been reported in at least 7 individuals with hypercholesterolemia, 1 individual with suspected hypercholesterolemia, 1 individual with hypertriglyceridemia, 1 individual with unspecified dyslipidemia, and 5 individuals with early myocardial infarction (MI) (Fouchier 2005 PMID: 16250003, Alonso 2009 PMID: 19318025, Guardamagna 2009 PMID: 19446849, Bertolini 2013 PMID: 23375686, Cymbron 2014 PMID: 25606447, Do 2015 PMID: 25487149, Thormaehlen 2015 PMID: 25647241, Sharifi 2016 PMID: 26892515, Sanchez-Hernandez 2019 PMID: 31153816, Dron 2020 PMID: 32041611, Gill 2021 PMID: 33303402). However, it was also observed in 4 MI-free controls in the same study (Do 2015 PMID: 25487149) and in one healthy control in another study of early-onset myocardial infarction (Khera 2019 PMID: 30586733). It has also been identified in 0.02% (3/15258) of Latine/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 161273). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant does not impact protein function (Thormaehlen 2015 PMID: 25647241, Benito-Vicente 2018 PMID: 30413722); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of the p.Thr62Met variant is uncertain. ACMG/AMP Criteria applied: PP3, BS3_supporting. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 04, 2023

Variant summary: LDLR c.185C>T (p.Thr62Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250804 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00012 vs 0.0013), allowing no conclusion about variant significance. c.185C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Fouchier_2005, Guardamagna_2009, Junyent_2010, Cymbron_2014, Sharifi_2016, Gill_2020). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Functional studies report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015, Benito-Vicente_2018, Graca_2020). The following publications have been ascertained in the context of this evaluation (PMID: 30413722, 25606447, 16250003, 33303402, 35568682, 19446849, 19717150, 34456049, 26892515, 25647241). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=11) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypercholesterolemia Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The p.T62M variant (also known as c.185C>T), located in coding exon 2 of the LDLR gene, results from a C to T substitution at nucleotide position 185. The threonine at codon 62 is replaced by methionine, an amino acid with similar properties. This variant has been reported in hypercholesterolemia cohorts but limited clinical information was provided (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Leigh SE et al. Ann. Hum. Genet., 2008 Jul;72:485-98; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). This variant has also been detected in exome cohorts and healthy controls with limited cardiovascular history (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Do R et al. Nature, 2015 Feb;518:102-6; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89). Limited functional studies have suggested no significant impact on LDLR expression, binding, or uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Benito-Vicente A et al. Sci Rep, 2018 Nov;8:16614). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.;.;.
Eigen	Benign	-0.0049
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.75	T;T;T;T;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.41	T;T;T;T;T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	-0.33	N;.;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.2	D;D;N;D;D;D
Sift	Benign	0.038	D;T;T;D;T;D
Sift4G	Uncertain	0.046	D;D;T;D;T;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.63
MVP		1.0
MPC		0.55
ClinPred		0.16	T
GERP RS		5.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.20
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: rs376207800; hg19: chr19-11211016;