Submissions for variant NM_015311.3(OBSL1):c.1273dup (p.Thr425fs)

gnomAD frequency: 0.00009  dbSNP: rs762334954

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790703	SCV000227439	pathogenic	not provided	2016-01-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000175869	SCV001360883	pathogenic	3M syndrome 2	2019-12-24	criteria provided, single submitter	clinical testing	Variant summary: OBSL1 c.1273dupA (p.Thr425AsnfsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 247272 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in OBSL1 causing 3-M syndrome 2 (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.1273dupA has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with 3-M syndrome 2 (e.g. Hanson_2009, Hu_2017). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000790703	SCV001791852	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19481195, 25923536, 27796265, 28969986, 29595812, 34597859, 19877176, 34426522, 31589614, 33258289, 33135300, 34006472)
Suma Genomics	RCV000175869	SCV001837622	pathogenic	3M syndrome 2		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000790703	SCV003272353	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr425Asnfs*40) in the OBSL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OBSL1 are known to be pathogenic (PMID: 19481195, 19877176). This variant is present in population databases (rs762334954, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with 3-M syndrome (PMID: 19481195, 25923536, 27796265). This variant is also known as c.1273insA, p.T45Nfs*40. ClinVar contains an entry for this variant (Variation ID: 195306). For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000175869	SCV003804434	pathogenic	3M syndrome 2	2023-02-23	criteria provided, single submitter	clinical testing	A heterozygous single base pair duplication in exon 2 of the OBSL1 gene that results in a frameshift and premature truncation of the protein 40 amino acids downstream to codon 425 (p.Thr425AsnfsTer40) was detected. The p.Thr425AsnfsTer40 variant has not been reported in the 1000 genomes databases and has a minor allele frequency of 0.01% in the gnomAD database. The in silico predictions of the variant are damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000175869	SCV004048304	pathogenic	3M syndrome 2		criteria provided, single submitter	clinical testing	The frameshift variant has been reported previously in homozygous state in a patient who presented with prenatal growth retardation and short stature (Keskin M. et al., 2019). This variant is reported with the allele frequency (0.02%) in the gnomad and novel in 1000 genome database. It has been submitted to the ClinVar as a Pathogenic variant. 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.
OMIM	RCV000175869	SCV000021250	pathogenic	3M syndrome 2	2009-06-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000175869	SCV000238469	pathogenic	3M syndrome 2	2015-06-10	no assertion criteria provided	research	The OBSL1 variant (c.1273dupA; p.T425fs) is considered pathogenic because it is a frameshift variant predicted to result in a truncated protein containing only one-third of the normal protein. This is a common OBSL1 variant associated with 3-M syndrome reported in 6 families (Huber et al. 2010, PMID 19877176) and 6 families (Hanson et al. 2009, PMID 19481195) mostly in the homozygous state in consanguineous families. This variant is present in 17 alleles out of 121632 alleles in ExAC. Another frameshift variant has been reported downstream of this position
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000790703	SCV001553568	pathogenic	not provided		no assertion criteria provided	clinical testing	The OBSL1 p.Thr425Asnfs*40 variant was identified in 25 of 50 proband chromosomes (frequency: 0.5) from 25 families with Miller-McKusick-Malvaux (3-M) syndrome (Hanson_2009_PMID:19481195; Huber_2010_PMID:19877176; Marshall_2015_PMID:25923536; Keskin_2017_PMID:27796265). The variant was identified in dbSNP (ID: rs762334954) and ClinVar (classifed as pathogenic by EGL Genetics, Division of Human Genetics, Children's Hospital of Philadelphia and OMIM) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 46 of 278660 chromosomes at a frequency of 0.000165 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 36 of 126596 chromosomes (freq: 0.000284), South Asian in 5 of 30580 chromosomes (freq: 0.000164), Latino in 4 of 35350 chromosomes (freq: 0.000113) and African in 1 of 24184 chromosomes (freq: 0.000041), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) or Other populations. The c.1273dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 425 and leads to a premature stop codon 40 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the OBSL1 gene are an established mechanism of disease in 3-M syndrome and are known to cause the disorder in the homozygous or compound heterozygous state. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Pediatric Endocrinology, Ankara Etlik City Hospital	RCV000175869	SCV003804426	pathogenic	3M syndrome 2		no assertion criteria provided	clinical testing	Molecular analysis of the OBSL1 gene identified a frameshift variant (c.1273dup; p.Thr425fs) in seven patients with clinical features consistent with 3M syndrome, six of whom were in homozygous and one was in compound heterozygous state. This variant results in a premature stop codon leading to truncation of the protein or nonsense mediated decay. Also, loss-of-function variants in OBSL1 gene have been determined to be deleterious. The detected variant has been associated with 3M syndrome in the literature previously. This variant was classified as pathogenic according to the ACMG guidelines.