rs28942079
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS3PS4PP1_StrongPM2PP3PP4PM3
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3, 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: PS3 - Level 1 FS: Chang et al., 2003 (PMID 12837857): Heterologous cells (COS), FACS and WB assays - results: 22% LDLR expression, 20% LDL-LDLR binding and internalization, LDLR retained in endosomal/lysosomal regions. Activity is below 70% of wild-type, so PS3 is met. PS4 - variant meets PM2 and was identified in - 7 unrelated index cases (1 index case with Simon Broome possible FH and 6 index cases 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;- 1 index case with Simon Broome possible FH (high chol in child w/ family hx) from Ambry Genetics, USA;- 1 index case with Simon Broome possible FH (LDL-C high, family history of high cholesterol) from GeneDx Inc, USA;- 47 unrelated index cases w/ Simon Broome possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal;- 1 index case with Simon Broome possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), reported in Tichy et al. 2012 PMID:22698793, Czech Republic;at least 57 unrelated cases, so PS4 is met.PP1_strong - variant segregates with FH phenotype in 72 informative meiosis from 28 families:- 10 informative meiosis from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): F1: 6 relatives with the variant have LDL >75th percentile, F2: 3 relatives with the variant have LDL >75th percentile, F3: 1 relative with the variant has LDL >75th percentile.- 28 informative meiosis from 14 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: in total, 21 relatives with the variant have LDL-C >75th percentile, and 7 relatives without the variant have LDL-C <50th percentile. The greatest # segregations occurring within a family is 5;- 34 informative meiosis from 11 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo: in total, 20 relatives with the variant have LDL-C >75th percentile, and 14 relatives without the variant have LDL-C <50th percentile. The greatest number of segregations occurring in a family was 9 (6 relatives positive for variant w/ phenotype, and 3 relatives negative for variant w/o phenotype).--- 72 informative meiosis support co-segregation, so PP1_Strong is metPM2 - PopMax MAF = 0.00005439 (0.005%) in East 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 homozygous for the variant under curation and untreated LDL = 512mg/dL from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.----- it is an homozygous patient with an homozygous phenotype, so PM3 is met.PP3 - REVEL = 0.914. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in at least 57 unrelated cases (see PS4 for details), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023445/MONDO:0007750/013
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)
Exomes 𝑓: 0.0000062 ( 1 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 8.01
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PS3
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.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1291G>A | p.Ala431Thr | missense_variant | 9/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.1291G>A | p.Ala431Thr | missense_variant | 9/18 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 29
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:30
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:21
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Ala431Thr (sometimes called p.Ala410Thr) variant in LDLR has been reported in at least 224 individuals (including 190 Dutch, 25 Portuguese, 2 Polish, 1 Greek, 1 Taiwanese, 1 Chinese, 1 Czech, and 1 Japanese individuals) with Familial Hypercholesterolemia (PMID: 20506408, 21382890, 17347910, 12837857, 22698793, 20538126, 20145306, 2088165, 10447263, 17765246, 15200491, 11810272), and has been identified in 0.005439% (1/18386) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942079). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 3695). Trio exome analysis showed this variant to be de novo in at least one individual reported in the literature (PMID: 17765246). In vitro functional studies provide some evidence that the p.Ala431Thr variant may impact protein function (PMID: 12837857, 2088165). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on a report of a de novo occurrence and multiple reports of this variant in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PS2, PS4, PS3_Moderate, PP3 (Richards 2015). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 17, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Aug 28, 2022 | The NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3, 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: PS3 - Level 1 FS: Chang et al., 2003 (PMID 12837857): Heterologous cells (COS), FACS and WB assays - results: 22% LDLR expression, 20% LDL-LDLR binding and internalization, LDLR retained in endosomal/lysosomal regions. Activity is below 70% of wild-type, so PS3 is met. PS4 - variant meets PM2 and was identified in - 7 unrelated index cases (1 index case with Simon Broome possible FH and 6 index cases 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; - 1 index case with Simon Broome possible FH (high chol in child w/ family hx) from Ambry Genetics, USA; - 1 index case with Simon Broome possible FH (LDL-C high, family history of high cholesterol) from GeneDx Inc, USA; - 47 unrelated index cases w/ Simon Broome possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 1 index case with Simon Broome possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), reported in Tichy et al. 2012 PMID: 22698793, Czech Republic; at least 57 unrelated cases, so PS4 is met. PP1_strong - variant segregates with FH phenotype in 72 informative meiosis from 28 families: - 10 informative meiosis from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): F1: 6 relatives with the variant have LDL >75th percentile, F2: 3 relatives with the variant have LDL >75th percentile, F3: 1 relative with the variant has LDL >75th percentile. - 28 informative meiosis from 14 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: in total, 21 relatives with the variant have LDL-C >75th percentile, and 7 relatives without the variant have LDL-C <50th percentile. The greatest # segregations occurring within a family is 5; - 34 informative meiosis from 11 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo: in total, 20 relatives with the variant have LDL-C >75th percentile, and 14 relatives without the variant have LDL-C <50th percentile. The greatest number of segregations occurring in a family was 9 (6 relatives positive for variant w/ phenotype, and 3 relatives negative for variant w/o phenotype). --- 72 informative meiosis support co-segregation, so PP1_Strong is met PM2 - PopMax MAF = 0.00005439 (0.005%) in East 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 homozygous for the variant under curation and untreated LDL = 512mg/dL from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. ----- it is an homozygous patient with an homozygous phenotype, so PM3 is met. PP3 - REVEL = 0.914. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in at least 57 unrelated cases (see PS4 for details), so PP4 is met. - |
| Likely 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 | subjects mutated among 2600 FH index cases screened = 4 , family members = 11 with co-segregation / FH-Algeria-2, 5 to 15% LDLR activity / Software predictions: Damaging - |
| Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| 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 | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/190 non-FH alleles; 0/100 Chinese normolipidemic individuals; 0/100 healthy control individuals - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 06, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | May 23, 2019 | - - |
| Pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 27, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 30, 2024 | ACMG classification criteria: PS3, PS4, PP1 strong, PM2, PM3, PP3, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 08, 2023 | This missense variant (also known as p.Ala410Thr in the mature protein) replaces alanine with threonine at codon 431 in the LDLR type B repeat 1 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a significant reduction in LDLR expression and activity in transfected COS-7 cells (PMID: 12837857). Another functional study using homozygous patient-derived fibroblasts has shown a significant reduction in LDLR activity compared to wild-type (PMID: 1301956). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 12837857, 21382890, 24627126, 25463123, 25461735, 27824480, 28104544, 29353225, 33994402). This variant has also been observed in homozygous as well as compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia, indicating that this variant contributes to disease (PMID: 1301956, 25461735, 26020417, 30270083). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (ClinVar SCV000322941.1, SCV000588572.1). This variant has been identified in 1/251286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia 1 (FH; MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous states with the recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 & v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Ala431Pro) has been classified as likely pathogenic by an expert panel in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PS4+PP4+PM3_Strong+PP1+PS3 - |
Familial hypercholesterolemia Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2023 | This missense variant (also known as p.Ala410Thr in the mature protein) replaces alanine with threonine at codon 431 in the LDLR type B repeat 1 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a significant reduction in LDLR expression and activity in transfected COS-7 cells (PMID: 12837857). Another functional study using homozygous patient-derived fibroblasts has shown a significant reduction in LDLR activity compared to wild-type (PMID: 1301956). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 12837857, 21382890, 24627126, 25463123, 25461735, 27824480, 28104544, 29353225, 33994402). This variant has also been observed in homozygous as well as compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia, indicating that this variant contributes to disease (PMID: 1301956, 25461735, 26020417, 30270083). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (ClinVar SCV000322941.1, SCV000588572.1). This variant has been identified in 1/251286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2020 | Variant summary: LDLR c.1291G>A (p.Ala431Thr) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251286 control chromosomes (gnomAD). c.1291G>A has been reported in the literature in multiple individuals, (in heterozygous, compound heterozygous and homozygous states), of different origins (e.g. Algerian, Chinese, Dutch, Greek, Japanese, Portuguese), affected with Familial Hypercholesterolemia (e.g. Bourbon_2008, Chang_2003, Dedoussis_2004, Hattori_1999, Hobbs_1992, Kusters_2013) and has been shown to co-segregate with disease in multiple families (e.g. Medeiros_2014, Mollaki_2014). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was reported to have considerably reduced LDLR activity compared to wild-type and was found to be retained in the endosomal/lysosomal region in contrast to the wild-type protein which localizes to the cell surface (Chang_ 2003, Hobbs_1992). Twelve ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 431 of the LDLR protein (p.Ala431Thr). This variant is present in population databases (rs28942079, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (FH) (PMID: 10447263, 12837857, 15200491, 17347910, 17765246, 21382890, 23815734, 25461735, 27824480, 28104544). This variant is also known as Ala410Thr (A410T). ClinVar contains an entry for this variant (Variation ID: 3695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 12837857). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH Algeria and A410T; This variant is associated with the following publications: (PMID: 2088165, 12837857, 10447263, 11810272, 28502495, 28104544, 25463123, 22698793, 20964105, 15200491, 22390909, 18718593, 27824480, 25461735, 21382890, 20145306, 17765246, 17347910, 31491741, 32977124, 32041611, 33740630, 34037665, 34456049, 35913489, 33955087, 33994402, 36464169, 32710294, 18239150, 24627126, 29353225, 23833242, 28391882, 30270055, 29874871) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 28, 2019 | The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2021 | The p.Ala431Thr variant in LDLR (also reported as FH-Algeria-2 in the literature) has been reported in at least 24 individuals with familial hypercholesterolemia (FH) and segregated with disease in > 14 affected relatives from at least one family (Hattori 1999, Chang 2003, Dedoussis 2004, Bourbon 2008, Huijgen 2012, Durst 2017). Additionally, this variant has been reported by other clinical laboratories in ClinVar (Variation ID: 3695) and has also been identified in 0.005% (1/18386) of East 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. In vitro functional studies support an impact on protein function (Hobbs 1990, Chang 2003) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PP3, PS3_Supporting. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2023 | The c.1291G>A (p.A431T) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1291, causing the alanine (A) at amino acid position 431 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (1/251286) total alleles studied. The highest observed frequency was 0.005% (1/18386) of East Asian alleles. This alteration (also referred to as p.A410T and FH Algeria) has been previously detected in the heterozygous, homozygous, and compound heterozygous states in multiple unrelated individuals from various ethnic backgrounds with diagnosed or suspected familial hypercholesterolemia (FH) (Hobbs, 1990; Hattori, 1999; Chang, 2003; Dedoussis, 2004; van der Graaf, 2011; Huijgen, 2012; Chiou, 2010; Medeiros, 2016). One study reported this alteration to account for 13% of genetically diagnosed FH cases in a cohort from Portugal, suggesting a possible founder effect (Bourbon, 2008). In addition, this alteration has been reported to result in reduced receptor activity and protein expression in vitro (Chang, 2003). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.;.;L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Gain of loop (P = 0.4248);Gain of loop (P = 0.4248);.;.;.;Gain of loop (P = 0.4248);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at