ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.376G>A (p.Asp126Asn) (rs104893831)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129380 SCV000184145 pathogenic Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000679037 SCV000292705 uncertain significance not provided 2015-06-12 criteria provided, single submitter clinical testing This variant is denoted VHL c.376G>A at the cDNA level, p.Asp126Asn (D126N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). VHL Asp126Asn was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. VHL Asp126Asn occurs at a position that is conserved across species and is located in the beta domain and in the region involved in binding to CCT complex (UniProt, Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. In vitro analyses have revealed this variant, when compared to wild-type, to have an intermediate effect on VHL function and to be expressed at lower levels in transfected cells (Bond 2011). Although this variant has not, to our knowledge, been published regarding its association with cancer in the heterozygous state, it has been published in the homozygous and compound heterozygous state to be associated with congenital polycythemia, severe erythrocytosis and pulmonary arterial hypertension (Sarangi 2014, Bond 2011). If this patientÂ’s partner is also a carrier of a pathogenic VHL variant associated with congenital polycythemia, severe erythrocytosis and pulmonary arterial hypertension, the risk to have a child with congenital polycythemia, severe erythrocytosis and pulmonary arterial hypertension is 25% for each pregnancy.In sum, VHL Asp126Asn has been reported in association with recessively-inherited congenital polycythemia, severe erythrocytosis and pulmonary arterial hypertension. However, with respect to increased cancer risk in heterozygous carriers, it is unclear whether VHL Asp126Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000631273 SCV000752301 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 126 of the VHL protein (p.Asp126Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs104893831, ExAC 0.009%). This variant has been reported as compound heterozygous with a p.Ser183Leu variant in an infant affected with erythrocytosis and pulmonary hypertension (PMID: 21454469) and as homozygous in another infant affected with polycythemia and pulmonary hypertension (PMID: 24729484). ClinVar contains an entry for this variant (Variation ID: 141044). This p.Asp126Asn variant may be associated only with recessively inherited erythrocytosis rather than with dominantly inherited von Hippel-Lindau syndrome, as is observed for the p.Arg200Trp variant causing Chuvash polycythemia (PMID: 11987242, 19494350, 9058738, 16210343). However, further studies are required to confirm this association. This variant has been reported to affect VHL protein function (PMID: 21454469, 30338240). 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.
Counsyl RCV000663314 SCV000786582 uncertain significance Von Hippel-Lindau syndrome 2018-05-29 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679037 SCV000805344 uncertain significance not provided 2015-11-03 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000663314 SCV000897812 uncertain significance Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland RCV000663314 SCV001160811 uncertain significance Von Hippel-Lindau syndrome 2019-12-11 criteria provided, single submitter research ACMG evidence PP3, PP5
OMIM RCV001007623 SCV001167311 pathogenic Erythrocytosis, familial, 2 2020-03-05 no assertion criteria provided literature only

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