Submissions for variant NM_000444.6(PHEX):c.1645+1G>A (rs886041225)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000336154	SCV000329462	pathogenic	not provided	2018-07-05	criteria provided, single submitter	clinical testing	The c.1645+1 G>A splice site variant in the PHEX gene has been previously reported in association with X-linked hypophosphatemic rickets (Filisetti et al., 1999; Holm et al., 2001; Gaucher et al., 2009). It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1645+1 G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Institute of Human Genetics, Klinikum rechts der Isar	RCV000505469	SCV000599641	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2017-06-12	criteria provided, single submitter	clinical testing
Invitae	RCV000336154	SCV001212864	pathogenic	not provided	2019-10-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 of the PHEX gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypophosphatemic rickets (PMID: 10439971, 24857004, 19219621, 18625346, Invitae). ClinVar contains an entry for this variant (Variation ID: 279871). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina	RCV000505469	SCV001451534	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2019-03-16	criteria provided, single submitter	clinical testing	The PHEX c.1645+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the available literature, the c.1645+1G>A variant has been identified in a heterozygous state in at least six individuals with a dominant form of X-linked hypophosphatemia, two of whom are related. The variant was proven to have arisen de novo in one individual (Filisetti et al. 1999; Holm et al. 2001; Ichikawa et al. 2008; Beck-Nielsen et al. 2012; Fahiminiya et al. 2014). Control data are unavailable for the c.1645+1G>A variant and is not found in the Genome Aggregation Database in a region of good sequencing coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the c.1645+1G>A variant is classified as pathogenic for X-linked hypophosphatemia.