Submissions for variant NM_016955.5(SEPSECS):c.808dup

dbSNP: rs776969714

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000396553	SCV000329514	pathogenic	not provided	2025-04-08	criteria provided, single submitter	clinical testing	Observed with a second variant on the opposite allele (in trans) in a patient with global developmental delay, hypotonia, cerebral atrophy, hypomyelination, and cortical visual impairment in the published literature (PMID: 31607746); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 34234304, 31607746)
Undiagnosed Diseases Network, NIH	RCV000625974	SCV000746575	pathogenic	Pontocerebellar hypoplasia type 2D	2017-04-06	criteria provided, single submitter	clinical testing	The c.808dupG variant in SEPSECS is a frameshift variant. The variant has been reported in other patient with similar phenotype. The variant was identifed as a compound heterozygote with c.846G>A that was shown by RNAseq to result in exon skipping that leads to a frameshift.
Eurofins Ntd Llc (ga)	RCV000396553	SCV000862743	likely pathogenic	not provided	2018-08-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000396553	SCV000935482	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala270Glyfs*5) in the SEPSECS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SEPSECS are known to be pathogenic (PMID: 25558065, 25590979, 26115735). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SEPSECS-related conditions. ClinVar contains an entry for this variant (Variation ID: 279890). For these reasons, this variant has been classified as Pathogenic.
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000396553	SCV001468945	pathogenic	not provided		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000625974	SCV002808717	pathogenic	Pontocerebellar hypoplasia type 2D	2024-05-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002519035	SCV003688410	pathogenic	Inborn genetic diseases	2022-06-21	criteria provided, single submitter	clinical testing	The c.808dupG (p.A270Gfs*5) alteration, located in exon 7 (coding exon 7) of the SEPSECS gene, consists of a duplication of G at position 808, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the GG allele has an overall frequency of <0.01% (5/281872) total alleles studied. The highest observed frequency was <0.01% (4/128848) of European (non-Finnish) alleles. This variant was confirmed in trans with a synonymous SEPSECS variant with a predicted splicing impact in a child with global developmental delay, cerebral atrophy, dyskinesia, hypotonia, myopathic facies, cortical visual impairment, and sleep disturbance (Lee, 2020). Based on the available evidence, this alteration is classified as pathogenic.