Submissions for variant NM_000527.5(LDLR):c.1061A>T (p.Asp354Val)

gnomAD frequency: 0.00003  dbSNP: rs755449669

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237971	SCV000295192	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771574	SCV000544673	pathogenic	Familial hypercholesterolemia	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 354 of the LDLR protein (p.Asp354Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 19837725). 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 Asp333Val. ClinVar contains an entry for this variant (Variation ID: 251640). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Asp354 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20145306, 20809525, 22698793). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Robarts Research Institute, Western University	RCV000237971	SCV000782907	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771574	SCV000904158	likely pathogenic	Familial hypercholesterolemia	2019-03-11	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp333Val in the mature protein) is located in the EGF-like repeat A in the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional assays have shown that this variant significantly reduces LDLR activity in cells from a heterozygous patient (PMID: 1301956). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 1301956, 17142622, 19837725). This variant has been identified in 2/30944 chromosomes (2/14980 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000771574	SCV000917588	pathogenic	Familial hypercholesterolemia	2024-11-22	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1061A>T (p.Asp354Val) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251190 control chromosomes (gnomAD). c.1061A>T has been reported in the literature in an individual affected with Familial Hypercholesterolemia who had reduced LDLR activity (Hobbs_1992, Khera_2019, Sturm_2021). These data indicate that the variant is very likely to be associated with disease. In addition, Other variants have been reported as pathogenic or likley pathogenic in the same codon, suggesting a functional role of the codon (c.1061A>G, p.Asp354Gly; c.1061A>C, p.Asp354Ala; c.1060G>A, p.Asp354Asn). The following publications have been ascertained in the context of this evaluation (PMID: 1301956, 30586733, 34037665, 19837725). ClinVar contains an entry for this variant (Variation ID: 251640). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000786347	SCV004039743	likely pathogenic	not provided	2024-07-18	criteria provided, single submitter	clinical testing	Identified in association with hypercholesterolemia and early-onset myocardial infarction in published literature and in ClinVar (PMID: 32220565, 1301956, 15556093, 19837725, 30586733, 32041611, 34037665); 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 p.(D333V) and FH Oklahoma; This variant is associated with the following publications: (PMID: 17142622, 1301956, 32041611, 15556093, 30586733, 34037665, 19837725, 32220565)
Ambry Genetics	RCV003380529	SCV004087482	likely pathogenic	Cardiovascular phenotype	2023-06-30	criteria provided, single submitter	clinical testing	The p.D354V variant (also known as c.1061A>T) is located in coding exon 8 of the LDLR gene. The aspartic acid at codon 354 is replaced by valine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 8. This variant (also referred to as p.D333V) has been detected in individuals and cohorts with familial hypercholesterolemia (FH), and in individuals undergoing genetic testing for suspicion of FH (Sozen M et al. Atheroscler Suppl, 2004 Dec;5:7-11; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Brown EE et al. J Clin Lipidol, 2020 Mar;14:331-338; Sturm AC et al. JAMA Cardiol, 2021 Aug;6:902-909; Ambry internal data). This variant was detected in an individual from an FH cohort demonstrating 15-30% LDLR activity who was indicated as being compound heterozygous for another, unidentified allele (Hobbs HH et al. Hum Mutat, 1992;1:445-66). Another alteration at the same codon, p.D354G (c.1061A>G, also referred to as p.D333G), has also been reported in association with FH (Mosig S et al. BMC Med Genomics. 2008 Nov;1:60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000237971	SCV005398671	pathogenic	Hypercholesterolemia, familial, 1	2022-02-02	criteria provided, single submitter	clinical testing	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 hypercholesterolemia (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic individuals have an earlier and more severe onset (GeneReviews). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium-binding EGF-like domain (NCBI). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternative changes at the same codon have been reported in multiple individuals with familial hypercholesterolemia (ClinVar, PMID: 29353225). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with familial hypercholesterolemia (ClinVar, PMID: 1301956). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using fibroblast has demonstrated reduced LDL receptor activity (PMID: 1301956). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000786347	SCV005413311	likely pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_moderate, PM5, PS3_supporting, PS4_supporting
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000786347	SCV005875508	pathogenic	not provided	2024-06-03	criteria provided, single submitter	clinical testing	The LDLR c.1061A>T; p.Asp354Val variant (rs755449669; ClinVar Variation ID: 251640) is reported in the literature in at least 10 individuals testing for clinical suspicion of familial hypercholesterolemia (FH) or associated findings (Hobbs 1991, Sozen 2004, Khera 2019, Dron 2020, Sturm 2021, Humphries 2006) , including one who met Dutch Lipid Clinical Network for probable FH (Brown 2020). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.981), and functional analyses of the variant protein show reduced recycling to the cell service following internalization (Class 5 mutation; Hobbs 1992). Based on available information, this variant is considered to be pathogenic References: Brown EE et al. Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia. J Clin Lipidol. 2020 May-Jun;14(3):331-338. PMID: 32220565. Dron JS et al. Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. BMC Med Genomics. 2020 Feb 10;13(1):23. PMID: 32041611 Hobbs HH et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Humphries SE et al. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006 Dec;43(12):943-9. PMID: 17142622 Khera AV et al. Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. Circulation. 2019 Mar 26;139(13):1593-1602. PMID: 30586733 Sozen M et al. Mutation detection in patients with familial hypercholesterolaemia using heteroduplex and single strand conformation polymorphism analysis by capillary electrophoresis. Atheroscler Suppl. 2004 Dec;5(5):7-11. PMID: 15556093. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237971	SCV000606312	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786347	SCV000925129	pathogenic	not provided	2017-02-09	no assertion criteria provided	provider interpretation	Genetic testing: The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB, PCSK9 and LDLRAP1. Results showed that the following variant was identified (see report below): p.Asp354Val (c.1061A>T) in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given case data, functional studies and other pathogenic variants at this same amino acid (p.Asp354Gly and p.Asp354Ala) we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least four unrelated cases of FH (not including this patient's family). There is good case data. This variant is historically known as p.Asp333Val. Hobbs, et al., 1992 (PMID: 1301956) reported this variant in a patient of American indian background and had 15-30 % of receptor activity. They classify this variant as a class 5, recycling defect allele. These bind and internalize ligands in coated pits, but fail to release the ligands in the endosome and thus do not recycle to the cell surface. They classify this variant as FH Oklahoma. Wittall, et al., 2010 (PMID: 19837725) reported this in one of their Greek patients with FH. Invitae has also seen this variant in multiple patients with FH. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 1.000). The Asp at codon 354 is conserved across species, as are neighboring amino acids. This variant is the first amino acid of the EGF-like 2 calcium binding domain. There is one individual with variation at codon 354 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. This indicates that variants at this position are rare.