NM_016955.4(SEPSECS):c.846G>A (p.Leu282=) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001462752.7

Allele description

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

Gene:

SEPSECS:Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p15.2

Genomic location:

Preferred name:

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

HGVS:

NC_000004.12:g.25145092C>T
NG_028222.1:g.20491G>A
NM_016955.4:c.846G>AMANE SELECT
NP_058651.3:p.Leu282=
NC_000004.11:g.25146714C>T
NM_016955.3:c.846G>A

Links:

dbSNP: rs146539065

NCBI 1000 Genomes Browser:

rs146539065

Molecular consequence:

NM_016955.4:c.846G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Functional consequence:

effect on RNA splicing [Variation Ontology: 0362]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001666677	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31607746, 35091508, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001666677

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 17, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

Lee H, Huang AY, Wang LK, Yoon AJ, Renteria G, Eskin A, Signer RH, Dorrani N, Nieves-Rodriguez S, Wan J, Douine ED, Woods JD, Dell'Angelica EC, Fogel BL, Martin MG, Butte MJ, Parker NH, Wang RT, Shieh PB, Wong DA, Gallant N, Singh KE, et al.

Genet Med. 2020 Mar;22(3):490-499. doi: 10.1038/s41436-019-0672-1. Epub 2019 Oct 14.

PubMed [citation]

PMID:: 31607746
PMCID:: PMC7405636

Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease.

Ramadesikan S, Hickey S, De Los Reyes E, Patel AD, Franklin SJ, Brennan P, Crist E, Lee K, White P, McBride KL, Koboldt DC, Wilson RK.

Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2). doi:pii: a006165. 10.1101/mcs.a006165. Print 2022 Feb.

PubMed [citation]

PMID:: 35091508
PMCID:: PMC8958912

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001666677.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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