VCV000374066.17 - ClinVar

NM_006846.4(SPINK5):c.891C>T (p.Cys297=)

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.

(10)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006846.4(SPINK5):c.891C>T (p.Cys297=)

Variation ID: 374066 Accession: VCV000374066.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q32 5: 148097875 (GRCh38) [ NCBI UCSC ] 5: 147477438 (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	Jan 16, 2017	Nov 24, 2024	May 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006846.4:c.891C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006837.2:p.Cys297=	synonymous
NM_001127698.2:c.891C>T	NP_001121170.1:p.Cys297=	synonymous
NM_001127699.2:c.891C>T	NP_001121171.1:p.Cys297=	synonymous
NC_000005.10:g.148097875C>T
NC_000005.9:g.147477438C>T
NG_009633.1:g.38904C>T
LRG_110:g.38904C>T
LRG_110t1:c.891C>T	LRG_110p1:p.Cys297=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000005.10:148097874:C:T

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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

ClinGen: CA3495406 dbSNP: rs752941297 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.
SPINK5		-	-	GRCh38 GRCh37	1037	1055

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.
Erythroderma Increased circulating IgE concentration	Likely pathogenic (1)	criteria provided, single submitter	Jul 13, 2015	RCV000415446.2
Netherton syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 16, 2024	RCV000806530.12
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 29, 2023	RCV000788305.6
Ichthyosis linearis circumflexa	Pathogenic (1)	criteria provided, single submitter	Jan 13, 2024	RCV003595957.2

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 (Jul 13, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Erythroderma Increased circulating IgE concentration Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492792.1 First in ClinVar: Jan 16, 2017 Last updated: Jan 16, 2017
Pathogenic (Aug 01, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Blueprint Genetics Accession: SCV000927364.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Primary Immunodeficiency Panel
Pathogenic (Jan 13, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ichthyosis linearis circumflexa Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000946534.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 22089833‚ 22377713‚ 25665175 Comment: This sequence change affects codon 297 of the SPINK5 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 297 of the SPINK5 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SPINK5 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs752941297, gnomAD 0.006%). This variant has been observed in individuals with Netherton syndrome (PMID: 22089833, 22377713). It is commonly reported in individuals of Greek ancestry (PMID: 22089833). ClinVar contains an entry for this variant (Variation ID: 374066). Studies have shown that this variant results in skipping of exon 11 and introduces a premature termination codon (PMID: 22089833, 22377713, 25665175). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Netherton syndrome Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367772.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Likely pathogenic.
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762255.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021	Clinical Features: Erythroderma (present) , Ichthyosis (present) , Hyperkeratosis (present) , Psoriasiform dermatitis (present) Sex: male
Pathogenic (Jun 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Netherton syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021945.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Netherton syndrome Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005090980.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024	Comment: PVS1_strong, PS3, PS4_mod, PM2- The variant is expected to result in an absent or disrupted protein product. It has been reported in ClinVar as Pathogenic … (more) PVS1_strong, PS3, PS4_mod, PM2- The variant is expected to result in an absent or disrupted protein product. It has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 374066). Low frequency in gnomAD population databases. (less)
Pathogenic (Nov 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198346.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Nov 29, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005201207.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Variant demonstrated to result in abnormal splicing leading to protein truncation in a gene for which loss of function is a known mechanism of disease … (more) Variant demonstrated to result in abnormal splicing leading to protein truncation in a gene for which loss of function is a known mechanism of disease (PMID: 22377713, 22089833, 25665175); Possible founder variant commonly reported in individuals of Greek ancestry (PMID: 22089833); This variant is associated with the following publications: (PMID: 34426522, 31589614, 34543653, 33534181, 26865388, 32767583, 28289593, 27905021, 25665175, 22089833, 22377713, 33890311, 29159247, 37834063, 28914264) (less)
Pathogenic (Apr 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Netherton syndrome Affected status: yes Allele origin: paternal	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV005413152.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024

Comment:

This sequence change affects codon 297 of the SPINK5 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SPINK5 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs752941297, gnomAD 0.006%). This variant has been observed in individuals with Netherton syndrome (PMID: 22089833, 22377713). It is commonly reported in individuals of Greek ancestry (PMID: 22089833). ClinVar contains an entry for this variant (Variation ID: 374066). Studies have shown that this variant results in skipping of exon 11 and introduces a premature termination codon (PMID: 22089833, 22377713, 25665175). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

PVS1_strong, PS3, PS4_mod, PM2- The variant is expected to result in an absent or disrupted protein product. It has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 374066). Low frequency in gnomAD population databases.

Comment:

Variant demonstrated to result in abnormal splicing leading to protein truncation in a gene for which loss of function is a known mechanism of disease (PMID: 22377713, 22089833, 25665175); Possible founder variant commonly reported in individuals of Greek ancestry (PMID: 22089833); This variant is associated with the following publications: (PMID: 34426522, 31589614, 34543653, 33534181, 26865388, 32767583, 28289593, 27905021, 25665175, 22089833, 22377713, 33890311, 29159247, 37834063, 28914264)

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

Title	Author	Journal	Year	Link
Exon-Specific U1s Correct SPINK5 Exon 11 Skipping Caused by a Synonymous Substitution that Affects a Bifunctional Splicing Regulatory Element.	Dal Mas A	Human mutation	2015	PMID: 25665175
A synonymous mutation in SPINK5 exon 11 causes Netherton syndrome by altering exonic splicing regulatory elements.	Fortugno P	Journal of human genetics	2012	PMID: 22377713
Clinical expression and new SPINK5 splicing defects in Netherton syndrome: unmasking a frequent founder synonymous mutation and unconventional intronic mutations.	Lacroix M	The Journal of investigative dermatology	2012	PMID: 22089833

Text-mined citations for rs752941297 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_006846.4(SPINK5):c.891C>T (p.Cys297=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs752941297 ...