19-11113348-C-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.1257C>G(p.Tyr419Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,654 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. Y419Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000527.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1257C>G | p.Tyr419Ter | stop_gained | 9/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1257C>G | p.Tyr419Ter | stop_gained | 9/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251248Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461654Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727138
GnomAD4 genome ? Cov.: 29
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 23, 2023 | This variant changes 1 nucleotide in exon 9 in the LDLR type B repeat 1 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11851376, 16183066, 19446849, 23375686, 26802169, 28965616, 31345425, 32977124, 33890362, 16183066, 33890362) and has been shown segregate with disease in multiple affected individuals from two Italian families (PMID: 16183066, 33890362). This variant has been identified in 1/251248 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
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 members = 9 with co-segregation / previously described in association with FH - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jun 05, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Familial hypercholesterolemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | This sequence change creates a premature translational stop signal (p.Tyr419*) 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). This variant is present in population databases (rs774439908, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 16183066, 28965616). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 251758). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 14, 2021 | Variant summary: LDLR c.1257C>G (p.Tyr419X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251248 control chromosomes. c.1257C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and subsequently included in other studies reporting overlapping cohorts (example, Pisciotta_2006, Pirillo_2017, Bertollini_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
LDLR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | The LDLR c.1257C>G variant is predicted to result in premature protein termination (p.Tyr419*). This variant, described using legacy nomenclature as p.Tyr398*, has been well-documented as pathogenic for familial hypercholesterolemia (Guardamagna et al. 2009. PubMed ID: 19446849; Pirillo et al. 2017. PubMed ID: 28965616). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 08, 2022 | The p.Y419* pathogenic mutation (also known as c.1257C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1257. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This variant (also referred to as p.Y398*) has been detected in several individuals with familial hypercholesterolemia and has shown segregation with disease in a family, although some reports may overlap (Van Gaal LF et al. Mol Cell Probes, 2001 Dec;15:329-36; Pisciotta L et al. Atherosclerosis, 2006 Jun;186:433-40; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Wintjens R et al. J Lipid Res, 2016 Mar;57:482-91; Giammanco A et al. Intern Med J, 2021 Apr;51:585-590). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at