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NM_016955.4(SEPSECS):c.1A>T (p.Met1Leu) AND Pontocerebellar hypoplasia type 2D

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 1, 2021
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:
RCV001725797.1

Allele description [Variation Report for NM_016955.4(SEPSECS):c.1A>T (p.Met1Leu)]

NM_016955.4(SEPSECS):c.1A>T (p.Met1Leu)

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.1A>T (p.Met1Leu)
HGVS:
  • NC_000004.12:g.25160369T>A
  • NG_028222.1:g.5214A>T
  • NM_016955.4:c.1A>TMANE SELECT
  • NP_058651.3:p.Met1Leu
  • NC_000004.11:g.25161991T>A
Protein change:
M1L
Links:
dbSNP: rs1025711998
NCBI 1000 Genomes Browser:
rs1025711998
Molecular consequence:
  • NM_016955.4:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_016955.4:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Pontocerebellar hypoplasia type 2D (PCH2D)
Synonyms:
Progressive cerebello-cerebral atrophy
Identifiers:
MONDO: MONDO:0013438; MedGen: C3151140; Orphanet: 247198; Orphanet: 2524; OMIM: 613811

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001960820Institute for Genomic Medicine, Nationwide Children's Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 1, 2021) 		maternalresearch

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedmaternalyes1not providednot providednot providednot providedresearch

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Institute for Genomic Medicine, Nationwide Children's Hospital, SCV001960820.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedresearch PubMed (1)

Description

This variant was identified compound-heterozygous with a splicing variant (ClinVar ID 522806) in two siblings with PCH type 2D. The c.1A>T variant is absent from public databases (0 in gnomAD despite good coverage), making it extremely rare. It disrupts the initiator codon of the canonical transcript and is predicted to change the starting methionine to a leucine (NM_016955.4:c.1A>T, (p.Met1Leu)). While this exact nucleotide change has not been previously reported to our knowledge, Zhu et al (PMID 25590979) identified a similar initiator codon variant (c.1A>G, (p.Met1Val)) that was compound-heterozygous with a splice site variant in a patient with PCH type 2D. We interpret the variant as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jul 29, 2024