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

dbSNP: rs1555354198

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000731602	SCV000859442	likely pathogenic	not provided	2018-03-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000731602	SCV001246127	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000731602	SCV001447719	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000731602	SCV002064140	pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000731602	SCV002228702	pathogenic	not provided	2024-10-08	criteria provided, single submitter	clinical testing	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 gene product 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.
Genetics and Molecular Pathology, SA Pathology	RCV000999506	SCV002556789	pathogenic	Neutropenia, severe congenital, 8, autosomal dominant	2021-03-05	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000999506	SCV004175773	pathogenic	Neutropenia, severe congenital, 8, autosomal dominant	2023-03-01	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000999506	SCV005086710	pathogenic	Neutropenia, severe congenital, 8, autosomal dominant	2024-09-19	criteria provided, single submitter	clinical testing	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
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004813105	SCV005438099	pathogenic	Ciliary dyskinesia, primary, 40	2024-12-17	criteria provided, single submitter	clinical testing
Molecular ImmunoRheumatology UMRS_1109, Institut national de la santé et de la recherche médicale	RCV000577900	SCV000583971	pathogenic	Shwachman-Diamond syndrome 1	2017-07-14	no assertion criteria provided	clinical testing
OMIM	RCV000999506	SCV001156153	pathogenic	Neutropenia, severe congenital, 8, autosomal dominant	2020-01-31	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000999506	SCV001469264	pathogenic	Neutropenia, severe congenital, 8, autosomal dominant	2020-06-07	no assertion criteria provided	clinical testing
GeneReviews	RCV000999506	SCV004035943	not provided	Neutropenia, severe congenital, 8, autosomal dominant		no assertion provided	literature only