Submissions for variant NM_000288.4(PEX7):c.340-10A>G

gnomAD frequency: 0.00006  dbSNP: rs267608255

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000032116	SCV000460534	uncertain significance	Phytanic acid storage disease	2016-06-14	criteria provided, single submitter	clinical testing	The c.340-10A>G variant has been reported in one study by Braverman et al. (2002) in which it was found in a compound heterozygous state in two unrelated individuals with rhizomelic chondrodysplasia punctata, one with a splice site variant and one with a stop-gained variant as the second allele. The c.340-10A>G variant was absent from at least 100 control chromosomes but is reported at a frequency of 0.00019 in the European (Non-Finnish) population of the Exome Aggregation Consortium. RT-PCR studies demonstrated that the c.340-10A>G variant produced lower levels of mRNA compared to wildtype, which is consistent with the milder disease phenotype in the patients. Based on the available evidence, the c.340-10A>G variant is classified as a variant of unknown significance but suspicious for pathogenicity for rhizomelic chondrodysplasia punctata.
Illumina Laboratory Services, Illumina	RCV000393497	SCV000460535	uncertain significance	Rhizomelic chondrodysplasia punctata type 1	2017-04-28	criteria provided, single submitter	clinical testing	The PEX7 c.340-10A>G variant is an intron variant that has been reported in one study by Braverman et al. (2002), in which it was found in a compound heterozygous state in two unrelated individuals with rhizomelic chondrodysplasia punctata. One of these individuals had a splice site variant as the second allele, and one had a stop-gained variant. The c.340-10A>G variant was absent from at least 100 control chromosomes and is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR studies demonstrated that the c.340-10A>G variant produced lower levels of mRNA compared to wildtype, which is consistent with the milder disease phenotype in the patients. Based on the available evidence, the c.340-10A>G variant is considered to be a variant of unknown significance but suspicious for pathogenicity for rhizomelic chondrodysplasia punctata. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Eurofins Ntd Llc (ga)	RCV000731239	SCV000859032	likely pathogenic	not provided	2017-12-29	criteria provided, single submitter	clinical testing
Invitae	RCV000008229	SCV001227539	pathogenic	Peroxisome biogenesis disorder 9B	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the PEX7 gene. It does not directly change the encoded amino acid sequence of the PEX7 protein. This variant is present in population databases (rs267608255, gnomAD 0.2%). This variant has been observed in individual(s) with rhizomelic chondrodysplasia punctata (PMID: 12325024). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS3-10A>G. ClinVar contains an entry for this variant (Variation ID: 7787). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000393497	SCV002041533	likely pathogenic	Rhizomelic chondrodysplasia punctata type 1	2024-02-22	criteria provided, single submitter	clinical testing	Variant summary: PEX7 c.340-10A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' splicing acceptor site, one predicts the variant weakens this site, and three predict the variant creates a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing presumably by nonsense mediated decay, although low levels of normal PEX7 transcript was also detected (Braverman_2002). The variant allele was found at a frequency of 0.00013 in 251386 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PEX7 causing Rhizomelic Chondrodysplasia Punctata Type 1 (0.00013 vs 0.0019), allowing no conclusion about variant significance. c.340-10A>G has been reported in the literature as a compound heterozygous genotype with other pathogenic variants in at-least two individuals, one affected with Rhizomelic Chondrodysplasia Punctata Type 1 and the other with milder features of adult Refsum disease (Braverman_2002). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12325024, 14974078, 25851898). ClinVar contains an entry for this variant (Variation ID: 7787). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000008229	SCV004201631	likely pathogenic	Peroxisome biogenesis disorder 9B	2023-10-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000731239	SCV004238335	likely pathogenic	not provided	2023-04-19	criteria provided, single submitter	clinical testing
OMIM	RCV000008229	SCV000028436	pathogenic	Peroxisome biogenesis disorder 9B	2002-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000032116	SCV000055656	not provided	Phytanic acid storage disease		no assertion provided	literature only
Natera, Inc.	RCV000393497	SCV001459666	likely pathogenic	Rhizomelic chondrodysplasia punctata type 1	2020-09-16	no assertion criteria provided	clinical testing