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NM_003031.4(SIAH1):c.361dup (p.Cys121fs) AND Buratti-Harel syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 23, 2022
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:
RCV004555198.1

Allele description [Variation Report for NM_003031.4(SIAH1):c.361dup (p.Cys121fs)]

NM_003031.4(SIAH1):c.361dup (p.Cys121fs)

Genes:
LONP2:lon peptidase 2, peroxisomal [Gene - OMIM - HGNC]
SIAH1:siah E3 ubiquitin protein ligase 1 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
16q12.1
Genomic location:
Preferred name:
NM_003031.4(SIAH1):c.361dup (p.Cys121fs)
HGVS:
  • NC_000016.10:g.48362068dup
  • NG_029599.1:g.28251dup
  • NG_053011.1:g.122902dup
  • NM_001006610.2:c.454dup
  • NM_001348078.2:c.*472dup
  • NM_003031.4:c.361dupMANE SELECT
  • NP_001006611.1:p.Cys152fs
  • NP_003022.3:p.Cys121fs
  • NC_000016.9:g.48395979dup
Protein change:
C121fs
Molecular consequence:
  • NM_001348078.2:c.*472dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001006610.2:c.454dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_003031.4:c.361dup - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

Condition(s)

Name:
Buratti-Harel syndrome
Identifiers:
MONDO: MONDO:0859144; MedGen: C5543351; OMIM: 619314

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005044154New York Genome Center - PrenatalSEQ
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Likely pathogenic
(Nov 23, 2022) 		de novoclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes1not providednot provided1not providedclinical testing

Details of each submission

From New York Genome Center - PrenatalSEQ, SCV005044154.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.361dup variant in SIAH1 has not previously been reported in the literature or public variant repositories (ClinVar and LOVD), and it is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases; however, there are other truncating variant carriers in exon 2 in gnomAD v2.1.1 dataset. The c.361dup variant in SIAH1 is located in exon 2 of this 2-exon gene, and is predicted to result in loss of >10% of this 282-amino acid long protein (p.Cys121LeufsTer2). Personal communication with an external expert provided previously unpublished clinical information of two individuals with neurodevelopmental disorders who were found to harbor de novo and not-maternally-inherited, respectively, truncating variants in exon 2. Based on recent evidence this de novo heterozygous c.361dup p.(Cys121LeufsTer2) variant identified in SIAH1 is classified here as Likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyes1not providednot provided1not providednot providednot provided

Last Updated: Aug 4, 2024