ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.12731C>G (p.Ser4244Cys)

gnomAD frequency: 0.00006  dbSNP: rs1052000878
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002375113 SCV002684775 uncertain significance Cardiovascular phenotype 2023-06-23 criteria provided, single submitter clinical testing The c.12731C>G (p.S4244C) alteration is located in exon 29 (coding exon 29) of the APOB gene. This alteration results from a C to G substitution at nucleotide position 12731, causing the serine (S) at amino acid position 4244 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002491583 SCV002777345 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2021-08-23 criteria provided, single submitter clinical testing
Invitae RCV002491583 SCV003782374 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2022-07-14 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 4244 of the APOB protein (p.Ser4244Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 928142). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
New York Genome Center RCV002491583 SCV003925088 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 2022-04-22 criteria provided, single submitter clinical testing The c.12731C>G variant in APOB has not previously been reported in the literature, however, it has been deposited in ClinVar as a Variant of Uncertain Significance for familial hypercholesterolemia [ClinVar ID: 928142]. The c.12731C>G variant is observed in 73 alleles (~0.009% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of US), suggesting it is not a common benign variant in the populations represented in those databases. The c.12731C>G variant is located in exon 29 of this 29-exon gene and predicted to replace serine amino acid with cysteine at position 4244 in alpha 3 domain of APOB protein (PMID: 19200547). In silico tools predict the p.(Ser4244Cys) variant to be benign [REVEL = 0.073]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.12731C>G p.(Ser4244Cys) variant identified in APOB is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003478726 SCV004221652 uncertain significance not provided 2023-04-24 criteria provided, single submitter clinical testing To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000087 (3/34502 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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