VCV003235937.1 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 3235937 Accession: VCV003235937.1

Type and length

Duplication, 1 bp

Location

Cytogenetic: 16q12.1 16: 48362067-48362068 (GRCh38) [ NCBI UCSC ] 16: 48395978-48395979 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 19, 2024	May 19, 2024	Nov 23, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_003031.4:c.361dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003022.3:p.Cys121fs	frameshift
NM_001006610.2:c.454dup	NP_001006611.1:p.Cys152fs	frameshift
NM_001348078.2:c.*472dup		3 prime UTR
NC_000016.10:g.48362068dup
NC_000016.9:g.48395979dup
NG_029599.1:g.28251dup
NG_053011.1:g.122902dup

... more HGVS ... less HGVS

Protein change

C121fs, C152fs

Other names

Canonical SPDI

NC_000016.10:48362067:A:AA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LONP2		-	-	GRCh38 GRCh37	26	77
SIAH1		-	-	GRCh38 GRCh37	5	53

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Buratti-Harel syndrome	Likely pathogenic (1)	criteria provided, single submitter	Nov 23, 2022	RCV004555198.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Nov 23, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Buratti-Harel syndrome Affected status: yes Allele origin: de novo	New York Genome Center Study: PrenatalSEQ Accession: SCV005044154.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Comment: 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 … (more) 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. (less) Clinical Features: Low-set ears (present) , Hand clenching (present) , Anteverted nares (present) , Overlapping fingers (present) Age: 20-29 weeks gestation Secondary finding: no

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...