Submissions for variant NM_000527.5(LDLR):c.1307T>C (p.Val436Ala)

gnomAD frequency: 0.00001  dbSNP: rs779732323

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV001063423	SCV000295357	likely pathogenic	Familial hypercholesterolemia	2016-03-25	criteria provided, single submitter	literature only	Re-evaluation of AGMC classification, scoring PP1_strong, PM2 and PS4_moderate. PP3 can not be scored as the REVEL value is 0.746 (below the >0.75 threshold).
GeneDx	RCV000489496	SCV000576707	likely pathogenic	not provided	2024-07-19	criteria provided, single submitter	clinical testing	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.(V415A); This variant is associated with the following publications: (PMID: 30270359, 9157944, 11810272, 21382890, 34407635, 33740630, 35928446, 9184256, 21722902, 37937776)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063423	SCV001228267	pathogenic	Familial hypercholesterolemia	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 436 of the LDLR protein (p.Val436Ala). This variant is present in population databases (rs779732323, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 9184256, 21382890, 21722902, 33740630; internal data). 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 V415A. ClinVar contains an entry for this variant (Variation ID: 251778). 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%. This variant disrupts the p.Val436 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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.
Color Diagnostics, LLC DBA Color Health	RCV001063423	SCV001733658	likely pathogenic	Familial hypercholesterolemia	2023-06-13	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Val415Ala in the mature protein) replaces valine with alanine in the LDLR type B repeat 1 at codon 436 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 40 individuals affected with familial hypercholesterolemia, including 42 Dutch carriers with LDL-C levels in the 75-88th percentile (PMID: 9184256, 21382890, 21722902, 34407635; Hartgers 2020, dissertation, University of Amsterdam). This variant has been reported to segregate with hypercholesterolemia in ten individuals from a Dutch family (PMID: 9184256). This variant has been identified in 4/282608 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
MGZ Medical Genetics Center	RCV000237902	SCV002579931	likely pathogenic	Hypercholesterolemia, familial, 1	2022-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372664	SCV004087471	likely pathogenic	Cardiovascular phenotype	2023-07-31	criteria provided, single submitter	clinical testing	The p.V436A variant (also known as c.1307T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1307. The valine at codon 436 is replaced by alanine, an amino acid with similar properties. This alteration, which is also known as p.V415A, has been identified in individuals with familial hypercholesterolemia (FH) and has been shown to co-segregate with disease in one large family (Lombardi P et al. Clin. Genet., 1997 Apr;51:286-7; Vaca G et al. Atherosclerosis. 2011 Oct;218(2):391-6; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Alver M et al. Genet. Med., 2019 05;21:1173-1180). A functional study detected partial reduction of LDLR protein expression in cells derived from a patient heterozygous for this alteration; however, the clinical significance of the observed decrease is unclear (Selberg O et al. J Appl Res., 2003;3:495-504). This amino acid position is not well 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.
All of Us Research Program, National Institutes of Health	RCV000237902	SCV004820295	likely pathogenic	Hypercholesterolemia, familial, 1	2024-01-05	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Val415Ala in the mature protein) replaces valine with alanine at codon 436 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 46 individuals affected with hypercholesterolemia, including 42 Dutch carriers with LDL-C levels in the 75-88th percentile (PMID: 9184256, 21382890, 21722902, 34407635; Hartgers 2020, dissertation, University of Amsterdam). This variant has been reported to segregate with hypercholesterolemia in ten individuals from a Dutch family (PMID: 9184256). This variant has been identified in 4/282608 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000237902	SCV004848346	likely pathogenic	Hypercholesterolemia, familial, 1	2020-03-10	criteria provided, single submitter	clinical testing	The p.Val436Ala variant in LDLR has been reported in 3 individuals with familial hypercholesterolemia and segregated with disease in 10 affected individuals from one family (Lombardi 1997, Vaca 2011, Alver 2019). It has also been identified in 0.003% (4/128976) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 251778). 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, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PP1_Strong, PM2, PP3, PS4_Supporting.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001063423	SCV005045747	likely pathogenic	Familial hypercholesterolemia	2021-10-01	criteria provided, single submitter	clinical testing	The c.1307T>C (p.Val436Ala) variant in the LDLR gene is located on the exon 9 and is predicted to replace valine with alanine at codon 436 (p.Val436Ala). The variant has been identified in 3 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 21382890, 21722902, 9184256). The variant segregates with FH phenotype in 10 informative meiosis in a family (PMID: 9184256). The variant has been reported in ClinVar (ID: 251778). The variant is rare in the general population according to gnomAD (4/282608). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.75). Therefore, the c.1307T>C (p.Val436Ala) variant of LDLR has been classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000489496	SCV005413313	likely pathogenic	not provided	2024-04-15	criteria provided, single submitter	clinical testing	PP1_moderate, PP3, PP4, PM2, PS4_moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001063423	SCV005886744	pathogenic	Familial hypercholesterolemia	2025-02-03	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1307T>C (p.Val436Ala) results in a non-conservative amino acid change located in the TolB, C-terminal domain (IPR011042) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251266 control chromosomes. c.1307T>C has been reported in the heterozygous state in the literature in multiple related individuals affected with Familial Hypercholesterolemia (example, Lombardi_1997) and segregated with disease. These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 9184256) .ClinVar contains an entry for this variant (Variation ID: 251778). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237902	SCV000606390	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Iberoamerican FH Network	RCV000237902	SCV000748053	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	flagged submission	research
Clinical Genetics, Academic Medical Center	RCV000489496	SCV001918014	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000489496	SCV001963063	pathogenic	not provided		no assertion criteria provided	clinical testing