rs745721296

chr2-21006189-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000384.3(APOB):c.10679A>G(p.Tyr3560Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y3560H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:4
• Conservation: PhyloP100: 2.63

Genes affected

APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 2-21006189-T-C is Pathogenic according to our data. Variant chr2-21006189-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265892.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=4, Pathogenic=1}. Variant chr2-21006189-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.10679A>G	p.Tyr3560Cys	missense_variant	26/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.10679A>G	p.Tyr3560Cys	missense_variant	26/29	1	NM_000384.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250954 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135602

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2022	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 31, 2020	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. -

Hypercholesterolemia, familial, 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.085	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.83
MVP		0.89
MPC		0.30
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.78

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: rs745721296; hg19: chr2-21229061;