Submissions for variant NM_016955.4(SEPSECS):c.846G>A (p.Leu282=)

gnomAD frequency: 0.00004  dbSNP: rs146539065

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000625975	SCV000746576	likely pathogenic	Pontocerebellar hypoplasia type 2D	2017-04-06	criteria provided, single submitter	clinical testing	The c.846G>A variant in SEPSECS was shown to result in exon skipping by RNAseq. The variant is present in 6 individuals in gnomAD as heterozygotes. The variant was identifed as a compound heterozygote with c.808dupG that is a frameshift variant.
Invitae	RCV001462752	SCV001666677	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change affects codon 282 of the SEPSECS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SEPSECS protein. This variant is present in population databases (rs146539065, gnomAD 0.02%). This variant has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 31607746, 35091508). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522806). 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	RCV001553762	SCV001774756	uncertain significance	not specified	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: SEPSECS c.846G>A alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 2.8e-05 in 250948 control chromosomes. c.846G>A has been reported in the literature in a 2-year-old female with severe hypotonia, global developmental delay with cerebral atrophy, hypomyelination, and central volume loss of the cerebrum who underwent trio genome sequencing and trio RNAseq from blood (Lee_2020). The patient was found to carry a paternal frameshift variant in SEPSECS (c.808dup) while the variant of interest was found on the maternal allele. RNAseq analysis showed the 130-bp exon 7 containing the synonymous variant (p. Leu282=) was skipped in about half of the mRNAs. The novel splice junction that joins exon 6 and exon 8 was detected in 25/695 additional unrelated samples without this variant, but at a much lower ratio compared with our proband and mother, suggesting that exon 7 may be susceptible to low-level skipping. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Institute for Genomic Medicine, Nationwide Children's Hospital	RCV000625975	SCV001960821	likely pathogenic	Pontocerebellar hypoplasia type 2D	2021-10-01	criteria provided, single submitter	research	This variant was identified in two siblings with PCH type 2D and was compound-heterozygous with an initiator codon variant (c.1A>T) considered to be pathogenic. Although the c.846G>A is a synonymous change, it has been shown to disrupt splicing in experimental work by the UDN (PMID: 31607746). It is extremely rare (AF~0.00004) with no homozygotes reported in public databases including gnomAD and TopMed. We interpret the variant as likely pathogenic.
Revvity Omics, Revvity	RCV000625975	SCV003819332	uncertain significance	Pontocerebellar hypoplasia type 2D	2021-10-12	criteria provided, single submitter	clinical testing