Submissions for variant NM_006214.4(PHYH):c.135-2A>G

gnomAD frequency: 0.00017  dbSNP: rs201578674

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599568	SCV000709949	pathogenic	not provided	2023-08-07	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 14974078, 25525159, 28470644, 9326939, 10767344, 18612766, 17905308, 31240149, 34426522, 32773395, 31816670)
Eurofins Ntd Llc (ga)	RCV000599568	SCV000859633	pathogenic	not provided	2018-02-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000660487	SCV000893156	pathogenic	Phytanic acid storage disease	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000660487	SCV000914450	pathogenic	Phytanic acid storage disease	2018-08-29	criteria provided, single submitter	clinical testing	The PHYH c.135-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.135-2A>G variant is described in four studies in which it has been detected in a total of ten individuals with Refsum disease, seven of whom carried the variant in a homozygous state and three in a compound heterozygous state (Mihalik et al. 1997; Jansen et al. 1997; Jansen et al. 2000; Finsterer et al. 2008). Mihalik et al. (1997) and Jansen et al., (1997) both identified the c.135-2A>G variant in a homozygous state in an individual with Refsum disease and found expression of a truncated mRNA due to exon skipping. The c.135-2A>G variant was found to alter the consensus splice acceptor site (Mihalik et al. 1997). Jansen et al. (2000) subsequently detected the c.135-2A>G variant in an additional six patients, all of whom had deficient PHYH activity in fibroblasts. Control information is unavailable for the c.135-2A>G variant which is reported at a frequency of 0.000245 in the European (non-Finnish) population of the Genome Aggregation Database. Heterologous expression in yeast demonstrated no detectable PHYH enzyme activity (Jansen et al. 2000). Immunoblotting experiments revealed a shorter protein and a reduction in protein expression compared to wild type suggesting that the c.135-2A>G variant protein is less stable and degrades more rapidly (Jansen et al. 2000). Based on the collective evidence, the c.135-2A>G variant is classified as pathogenic for Refsum disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000599568	SCV001418669	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the PHYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs201578674, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with clinical features of Refsum disease (PMID: 9326939, 17905308, 31240149). ClinVar contains an entry for this variant (Variation ID: 7581). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 9326939). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000599568	SCV001713535	pathogenic	not provided	2021-01-19	criteria provided, single submitter	clinical testing	PVS1, PS3, PS4_moderate, PM2, PM3, PP1
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723551	SCV001950326	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The c.135-2A>G variant in PHYH was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Baylor Genetics	RCV000660487	SCV004204007	pathogenic	Phytanic acid storage disease	2024-03-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814858	SCV005069110	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000660487	SCV005184547	pathogenic	Phytanic acid storage disease	2024-05-28	criteria provided, single submitter	clinical testing	Variant summary: PHYH c.135-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. The variant allele was found at a frequency of 0.0001 in 250504 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PHYH causing Phytanic Acid Storage Disease, allowing no conclusion about variant significance. c.135-2A>G has been reported in the literature in multiple individuals affected with Phytanic Acid Storage Disease (e.g. Dubot_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31240149). ClinVar contains an entry for this variant (Variation ID: 7581). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000008019	SCV000028224	pathogenic	REFSUM DISEASE, ADULT, 1	2000-05-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003407301	SCV004115221	pathogenic	PHYH-related disorder	2024-02-09	no assertion criteria provided	clinical testing	The PHYH c.135-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the homozygous state in two unrelated patients with Refsum disease, and functional studies demonstrated this variant leads to exon skipping (Mihalik. 1997. PubMed ID: 9326939; Dubot. 2019. PubMed ID: 31240149). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in PHYH are expected to be pathogenic. This variant is interpreted as pathogenic.