NM_000527.5:c.1291G>A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM2PM3PP3PP4PP1_StrongPS3PS4
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
Consequence
NM_000527.5 missense
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 rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1291G>A | p.Ala431Thr | missense_variant | Exon 9 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251286Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461676Hom.: 1 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727150
GnomAD4 genome 0.00000657 AC: 1AN: 152274Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 74450
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:21
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 -
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ACMG classification criteria: PS3, PS4, PP1 strong, PM2, PM3, PP3, PP4 -
PS4+PP4+PM3_Strong+PP1+PS3 -
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0/190 non-FH alleles; 0/100 Chinese normolipidemic individuals; 0/100 healthy control individuals -
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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). -
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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 -
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. -
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. -
Familial hypercholesterolemia Pathogenic:4
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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. -
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. -
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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as Ala410Thr (A410T). ClinVar contains an entry for this variant (Variation ID: 3695). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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
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) -
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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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at