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 2020-09-17 criteria provided, single submitter clinical testing ​The p.D126N pathogenic mutation (also known as c.376G>A) is located in coding exon 2 of the VHL gene. This alteration results from a G to A substitution at nucleotide position 376. The aspartic acid at codon 126 is replaced by asparagine, an amino acid with highly similar properties. The p.D126N mutation has been shown to cause autosomal recessive polycythemia, a condition characterized by increased red blood cell mass and high risk of pulmonary hypertension, peripheral thrombosis and cerebrovascular events (Bond, J et al. Blood. 2011 Mar 31;117(13):3699-701). This alteration has been reported in the homozygous state in a 7-month-old boy with polycythemia, developmental delay, and severe early onset pulmonary hypertension (Sarangi S et al. Pediatr Blood Cancer 2014 Nov;61(11):2104-6). This alteration was also identified in a child with congenital pulmonary arterial hypertension, along with a second VHL variant, p.S183L; functional studies on both variants found that they both impair the ability of VHL to regulate hypoxia-inducible factors (HIF) (Bond, J et al. Blood. 2011 Mar 31;117(13):3699-701). To date, this variant has not been associated in the literature with VHL disease, although it has been identified in three families with a history of pheochromocytomas (Ambry internal data). Internal structural analysis reveals that this variant is anticipated to result in a decrease in structural stability (Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, p.D126N is interpreted as a disease-causing mutation. At this time, individuals who are heterozygous for the p.D126N alteration can be interpreted as carriers for autosomal recessive polycythemia, however, the clinical implications of this alteration with respect to von Hippel-Lindau disease have not been determined.
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 2020-08-21 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
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,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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