Submissions for variant NM_000384.3(APOB):c.10679A>G (p.Tyr3560Cys)

gnomAD frequency: 0.00001  dbSNP: rs745721296

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000256302	SCV000322855	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Invitae	RCV001837818	SCV000659250	pathogenic	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3560 of the APOB protein (p.Tyr3560Cys). This variant is present in population databases (rs745721296, gnomAD 0.009%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 18325181, 20828696, 21722902, 28895539; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Tyr3533Cys. ClinVar contains an entry for this variant (Variation ID: 265892). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APOB protein function. For these reasons, this variant has been classified as Pathogenic.
Iberoamerican FH Network	RCV000256302	SCV000748033	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284731	SCV001470677	likely pathogenic	not provided	2020-07-31	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV001450045	SCV001653669	likely pathogenic	Hypercholesterolemia, autosomal dominant, type B	2021-05-24	criteria provided, single submitter	clinical testing
Mendelics	RCV001450045	SCV002516226	likely pathogenic	Hypercholesterolemia, autosomal dominant, type B	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001450045	SCV002600850	likely pathogenic	Hypercholesterolemia, autosomal dominant, type B	2023-11-14	criteria provided, single submitter	clinical testing	Variant summary: APOB c.10679A>G (p.Tyr3560Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of three 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 250954 control chromosomes (gnomAD). c.10679A>G has been reported in the literature in multiple individuals affected with Familial Defective Apolipoprotein B/Familial Hypercholesterolaemia (example, Medeiros_2010, Liyange_2008, Vaca_2011, Medeiros_2014, Futema_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18325181, 21722902, 24627126, 33508743, 20828696). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=4), likely pathogenic (n=4) and pathogenic (n=1). Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002411134	SCV002719177	uncertain significance	Cardiovascular phenotype	2023-03-16	criteria provided, single submitter	clinical testing	The p.Y3560C variant (also known as c.10679A>G), located in coding exon 26 of the APOB gene, results from an A to G substitution at nucleotide position 10679. The tyrosine at codon 3560 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in several individuals diagnosed with familial hypercholesterolemia (Lima-Martínez MM et al. Endocrinol Diabetes Nutr, 2017 Oct;64:432-439; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Liyanage KE et al. Ann Clin Biochem, 2008 Mar;45:170-6). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001284731	SCV003799494	likely pathogenic	not provided	2022-10-19	criteria provided, single submitter	clinical testing	The APOB c.10679A>G; p.Tyr3560Cys variant (rs745721296), also known as Y3533C, is reported in the literature in multiple individuals with diagnosed or suspected familial hypercholesterolemia (Lima-Martínez 2017, Liyanage 2008, Medeiros 2010, Sturm 2021, Vaca 2011). This variant is also reported in ClinVar (Variation ID: 265892) and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 3533 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.678). Based on available information, this variant is considered to be likely pathogenic. References: Lima-Martínez MM et al. Frequency and clinical and molecular aspects of familial hypercholesterolemia in an endocrinology unit in Ciudad Bolívar, Venezuela. Endocrinol Diabetes Nutr. 2017 Oct;64(8):432-439. English, Spanish. PMID: 28895539. Liyanage KE et al. High-resolution melting analysis for detection of familial ligand-defective apolipoprotein B-100 mutations. Ann Clin Biochem. 2008 Mar;45(Pt 2):170-6. PMID: 18325181. Medeiros AM et al. Update of the Portuguese Familial Hypercholesterolaemia Study. Atherosclerosis. 2010 Oct;212(2):553-8. PMID: 20828696. 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. Vaca G et al. Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia. Atherosclerosis. 2011 Oct;218(2):391-6. Epub 2011 Jun 13. PMID: 21722902.
GeneDx	RCV001284731	SCV003921675	uncertain significance	not provided	2022-10-26	criteria provided, single submitter	clinical testing	Identified in patients with FH in published literature (Medeiros et al., 2010; Vaca et al., 2011; Lima-Martinez et al., 2017; Sturm et al., 2021; Di Taranto et al., 2021); 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.(Y3533C); This variant is associated with the following publications: (PMID: 30710474, 18325181, 34037665, 28895539, 21722902, 34297352, 20828696)