ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.1404G>C (p.Lys468Asn)

dbSNP: rs754449807
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV000505436 SCV000599663 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2013-11-06 criteria provided, single submitter clinical testing
Invitae RCV001377690 SCV001575083 likely pathogenic not provided 2021-04-13 criteria provided, single submitter clinical testing 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with hypophosphatemic rickets (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438531). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces lysine with asparagine at codon 468 of the PHEX protein (p.Lys468Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon.

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