Submissions for variant NM_000444.6(PHEX):c.2138dup (p.Gln714fs)

dbSNP: rs886041375

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000311640	SCV000329890	likely pathogenic	not provided	2017-03-14	criteria provided, single submitter	clinical testing	The c.2138dupC variant in the PHEX gene has been reported previously in association with Hypophosphatemic Rickets (Gaucher et al., 2009). The c.2138dupC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The duplication causes a frameshift starting with codon Glutamine 714, changes this amino acid to a Serine residue and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Gln714SerfsX3. This alteration is predicted to cause loss of normal protein function through protein truncation. Specifically, it is predicted that the last 36 correct amino acids will be lost and replaced by 2 incorrect amino acids. Therefore, this variant is likely pathogenic.
Invitae	RCV000311640	SCV003444632	pathogenic	not provided	2023-04-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PHEX protein in which other variant(s) (p.Arg747*) have been determined to be pathogenic (PMID: 9199930, 9768674). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 280088). This variant is also known as c.2138_2139insC; p.Pro713ProfsX4 . This premature translational stop signal has been observed in individual(s) with hypophosphatemia (PMID: 19219621, 32329911). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln714Serfs*3) in the PHEX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the PHEX protein.