VCV000430852.44 - ClinVar

NM_003136.4(SRP54):c.343ACA[2] (p.Thr117del)

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.

(12)

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_003136.4(SRP54):c.343ACA[2] (p.Thr117del)

Variation ID: 430852 Accession: VCV000430852.44

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 14q13.2 14: 35007369-35007371 (GRCh38) [ NCBI UCSC ] 14: 35476575-35476577 (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 27, 2018	Nov 24, 2024	Sep 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003136.4:c.343ACA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003127.1:p.Thr117del	inframe deletion
NM_003136.4:c.349_351del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001146282.2:c.196ACA[2]	NP_001139754.1:p.Thr68del	inframe deletion
NM_003136.3:c.349_351delACA
NC_000014.9:g.35007370ACA[2]
NC_000014.8:g.35476576ACA[2]

... more HGVS ... less HGVS

Protein change

T117del, T68del

Other names

Canonical SPDI

NC_000014.9:35007368:AACAACAACA:AACAACA

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

ClinGen: CA658658253 OMIM: 604857.0003 dbSNP: rs1555354198 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.
SRP54		-	-	GRCh38 GRCh37	249	277

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.
Shwachman-Diamond syndrome 1	Pathogenic (1)	no assertion criteria provided	Jul 14, 2017	RCV000577900.4
Neutropenia, severe congenital, 8, autosomal dominant	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Sep 19, 2024	RCV000999506.10
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 30, 2023	RCV000731602.34

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 (Mar 23, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000859442.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Publications: PubMed (1) PubMed: 28972538 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SRP54 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447719.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Neutropenia (present) Sex: male
Pathogenic (Mar 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neutropenia, severe congenital, 8, autosomal dominant (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556789.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022
Pathogenic (Jan 18, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002064140.2 First in ClinVar: Jan 29, 2022 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; Published functional studies suggest a damaging effect (Carapito … (more) Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; Published functional studies suggest a damaging effect (Carapito et al., 2017); This variant is associated with the following publications: (PMID: 28972538, 29956078, 29914977, 32277798, 32196641, 32135276, 32054657, 33726816, 33053321) (less)
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neutropenia, severe congenital, 8, autosomal dominant (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004175773.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: The inframe deletion c.349_351del (p.Thr117del) variant in SRP54 gene has been previously reported in heterozygous state in multiple individuals affected with Severe Congenital Neutropenia (Carapito … (more) The inframe deletion c.349_351del (p.Thr117del) variant in SRP54 gene has been previously reported in heterozygous state in multiple individuals affected with Severe Congenital Neutropenia (Carapito et al., 2017; Bellanné-Chantelot et al., 2018; Carden et al., 2018). Experimental studies indicate that this variant affects SRP54 function (Carapito et al., 2017). The p.Thr117del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This p.Thr117del causes deletion of amino acid Threonine at position 117. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002228702.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 28972538‚ 29914977‚ 29956078 Comment: This variant, c.349_351del, results in the deletion of 1 amino acid(s) of the SRP54 protein (p.Thr117del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.349_351del, results in the deletion of 1 amino acid(s) of the SRP54 protein (p.Thr117del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital neutropenia and Shwachman-Diamond-like syndrome (PMID: 28972538, 29914977, 29956078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430852). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SRP54 function (PMID: 28972538). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246127.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Sep 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neutropenia, severe congenital, 8, autosomal dominant (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086710.2 First in ClinVar: Jul 23, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 29914977‚ 33227812 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant-negative is the suggested mechanism (PMID: 33227812). (I) 0107 - This gene is associated with autosomal dominant disease. Variants expected to interact with the G1 element of the GTPase domain are associated with severe congenital neutropenia 8 (MIM#618752), while variants located elsewhere are associated with Shwachman-Diamond syndrome, SRP54-related (MONDO#0009833) (PMID: 29914977). (I) 0214 - In-frame insertion/deletion fully contained in a repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated GTPase domain (PMID: 29914977). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant reported in several individuals with chronic neutropenia, including de novo events (PMID: 29914977; ClinVar). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jul 14, 2017)	no assertion criteria provided Method: clinical testing	Shwachman-Diamond syndrome 1 Affected status: yes Allele origin: de novo	Molecular ImmunoRheumatology UMRS_1109, Institut national de la santé et de la recherche médicale Accession: SCV000583971.1 First in ClinVar: Jan 27, 2018 Last updated: Jan 27, 2018	Publications: PubMed (1) PubMed: 28972538
Pathogenic (Jan 31, 2020)	no assertion criteria provided Method: literature only	NEUTROPENIA, SEVERE CONGENITAL, 8, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV001156153.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Publications: PubMed (2) PubMed: 28972538‚ 29914977 Comment on evidence: In an 18-year-old man (family C) with autosomal dominant severe congenital neutropenia-8 (SCN8; 618752), Carapito et al. (2017) identified a de novo heterozygous 3-bp in-frame … (more) In an 18-year-old man (family C) with autosomal dominant severe congenital neutropenia-8 (SCN8; 618752), Carapito et al. (2017) identified a de novo heterozygous 3-bp in-frame deletion (c.349_351del, NM_003136.3) in the SRP54 gene, resulting in the deletion of highly conserved residue thr117 (Thr117del) in the GTPase domain. The authors stated that the mutation occurred in exon 4. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the 1000 Genomes Project or ExAC databases, or in various other databases containing more than 100,000 exomes. In vitro studies showed that the GTPase activity of the mutant protein was moderately decreased by about 1.6-fold compared to controls. Bellanne-Chantelot et al. (2018) identified a heterozygous Thr117del (c.349_351del, NM_003136.3) mutation in the SRP54 gene in 14 French patients with SCN8. The mutation occurred de novo in 7 patients and was inherited from an affected (2) or unaffected mosaic parent (1) in 3 cases; inheritance could not be determined in the 2 remaining cases. These authors stated that the mutation occurred in exon 5. (less)
Pathogenic (Jun 07, 2020)	no assertion criteria provided Method: clinical testing	Neutropenia, severe congenital, 8, autosomal dominant Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469264.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
not provided (-)	no classification provided Method: literature only	Neutropenia, severe congenital, 8, autosomal dominant Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV004035943.1 First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023	Publications: PubMed (1) PubMed: 28972538 Bookshelf: NBK1756 Bookshelf: NBK1756
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Comment:

Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; Published functional studies suggest a damaging effect (Carapito et al., 2017); This variant is associated with the following publications: (PMID: 28972538, 29956078, 29914977, 32277798, 32196641, 32135276, 32054657, 33726816, 33053321)

Comment:

The inframe deletion c.349_351del (p.Thr117del) variant in SRP54 gene has been previously reported in heterozygous state in multiple individuals affected with Severe Congenital Neutropenia (Carapito et al., 2017; Bellanné-Chantelot et al., 2018; Carden et al., 2018). Experimental studies indicate that this variant affects SRP54 function (Carapito et al., 2017). The p.Thr117del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This p.Thr117del causes deletion of amino acid Threonine at position 117. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant, c.349_351del, results in the deletion of 1 amino acid(s) of the SRP54 protein (p.Thr117del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital neutropenia and Shwachman-Diamond-like syndrome (PMID: 28972538, 29914977, 29956078). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430852). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SRP54 function (PMID: 28972538). For these reasons, this variant has been classified as Pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant-negative is the suggested mechanism (PMID: 33227812). (I) 0107 - This gene is associated with autosomal dominant disease. Variants expected to interact with the G1 element of the GTPase domain are associated with severe congenital neutropenia 8 (MIM#618752), while variants located elsewhere are associated with Shwachman-Diamond syndrome, SRP54-related (MONDO#0009833) (PMID: 29914977). (I) 0214 - In-frame insertion/deletion fully contained in a repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated GTPase domain (PMID: 29914977). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant reported in several individuals with chronic neutropenia, including de novo events (PMID: 29914977; ClinVar). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Shwachman-Diamond Syndrome.	Adam MP	-	2024	PMID: 20301722
SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing.	Schürch C	Blood	2021	PMID: 33227812
Severe Congenital Neutropenia associated with SRP54 mutation in 22q11.2 Deletion Syndrome: Hematopoietic Stem Cell Transplantation Results in Correction of Neutropenia with Adequate Immune Reconstitution.	Carden MA	Journal of clinical immunology	2018	PMID: 29956078
Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.	Bellanné-Chantelot C	Blood	2018	PMID: 29914977
Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.	Carapito R	The Journal of clinical investigation	2017	PMID: 28972538
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SRP54	-	-	-	-

Text-mined citations for rs1555354198 ...

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 30, 2024

ClinVar Genomic variation as it relates to human health

NM_003136.4(SRP54):c.343ACA[2] (p.Thr117del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555354198 ...