Submissions for variant NM_016955.4(SEPSECS):c.388+3A>G

gnomAD frequency: 0.00005  dbSNP: rs757504141

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000428576	SCV000514603	likely pathogenic	not provided	2023-08-19	criteria provided, single submitter	clinical testing	In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29709707, 25590979)
Baylor Genetics	RCV001333939	SCV001526655	uncertain significance	Pontocerebellar hypoplasia type 2D	2022-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265757	SCV002547490	uncertain significance	not specified	2025-03-17	criteria provided, single submitter	clinical testing	Variant summary: SEPSECS c.388+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5 splicing donor site. Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.8e-05 in 251424 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SEPSECS causing Pontocerebellar Hypoplasia, Type 2D (6.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.388+3A>G has been reported in the literature as a compound heterozygous genotype in at least one individual affected with Pontocerebellar Hypoplasia, Type 2D who underwent trio based whole exome sequencing (e.g., Zhu_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25590979). ClinVar contains an entry for this variant (Variation ID: 378569). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000428576	SCV003257277	uncertain significance	not provided	2021-08-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the SEPSECS gene. It does not directly change the encoded amino acid sequence of the SEPSECS protein. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs757504141, ExAC 0.02%). This variant has been observed in individuals with hypotonia, global DD, microcephaly with progressive cerebellar and vermian atrophy (PMID: 25590979). ClinVar contains an entry for this variant (Variation ID: 378569). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV001333939	SCV003919027	likely pathogenic	Pontocerebellar hypoplasia type 2D	2023-04-20	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV001333939	SCV005662133	likely pathogenic	Pontocerebellar hypoplasia type 2D	2024-05-16	criteria provided, single submitter	clinical testing