chr19-11113382-G-A

Position:

• chr19-11113382-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS3 PS4 PP1_Strong PM2 PP3 PP4 PM3

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
• Clinical Significance: Pathogenic reviewed by expert panel P:30
• 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]

LDLR (HGNC:):

ACMG classification

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 AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251286 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461676 Hom.: 1 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152274 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30

Revision: reviewed by expert panel

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.7	L;.;.;.;.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.56
MutPred		0.92		Gain of loop (P = 0.4248);Gain of loop (P = 0.4248);.;.;.;Gain of loop (P = 0.4248);
MVP		1.0
MPC		0.77
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.99

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: rs28942079; hg19: chr19-11224058;