Submissions for variant NM_015311.3(OBSL1):c.4133C>T (p.Thr1378Met)

gnomAD frequency: 0.00009  dbSNP: rs200449388

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001138065	SCV001298090	uncertain significance	3M syndrome 2	2018-03-02	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001357807	SCV001562092	uncertain significance	not provided	2022-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1378 of the OBSL1 protein (p.Thr1378Met). This variant is present in population databases (rs200449388, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with OBSL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 895776). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002558307	SCV003642186	uncertain significance	Inborn genetic diseases	2021-10-29	criteria provided, single submitter	clinical testing	The c.4133C>T (p.T1378M) alteration is located in exon 13 (coding exon 13) of the OBSL1 gene. This alteration results from a C to T substitution at nucleotide position 4133, causing the threonine (T) at amino acid position 1378 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV001357807	SCV004151475	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	OBSL1: PM2, BP4
Revvity Omics, Revvity	RCV001138065	SCV004235675	uncertain significance	3M syndrome 2	2023-11-06	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001357807	SCV005188325	uncertain significance	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357807	SCV001553391	uncertain significance	not provided		no assertion criteria provided	clinical testing	The OBSL1 p.T1378M variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs200449388) and in control databases in 33 of 280344 chromosomes at a frequency of 0.0001177 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 7130 chromosomes (freq: 0.000281), European (non-Finnish) in 26 of 128220 chromosomes (freq: 0.000203), Latino in 4 of 35326 chromosomes (freq: 0.000113) and South Asian in 1 of 30588 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.T1378 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.