ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.370A>G (p.Thr124Ala) (rs1559428091)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000707189 SCV000836274 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-07-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 124 of the VHL protein (p.Thr124Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in trans with another VHL variant in two individuals of a family affected with congenital polycythemia (PMID: 23772956). Experimental studies have shown that this missense change reduces protein stability (PMID: 23772956). A different missense substitution at this codon (p.Thr124Ile) has been reported in an individual affected with von Hippel-Lindau syndrome (PMID: 12624160). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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