Submissions for variant NM_001395891.1(CLASP1):c.196-567G>A

gnomAD frequency: 0.00038  dbSNP: rs559979281

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000202315	SCV000837725	pathogenic	Roifman syndrome	2019-10-02	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788934	SCV000928232	pathogenic	not provided	2019-02-18	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000788934	SCV001446768	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000788934	SCV001746666	pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	RNU4ATAC: PM3:Very Strong, PM2, PP1:Moderate, PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000788934	SCV002222473	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs559979281, gnomAD 0.06%). This variant has been observed in individual(s) with Roifman syndrome (PMID: 26522830, 28623346, 30455926, 32109076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218083). Functional studies have shown that this variant disrupts ncRNA function (PMID: 32628740). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002478721	SCV002794997	pathogenic	Osteodysplastic primordial dwarfism, type 1; Lowry-Wood syndrome; Roifman syndrome	2022-03-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000788934	SCV004026341	pathogenic	not provided	2023-04-19	criteria provided, single submitter	clinical testing	PS4_MOD, PP1, PS3, PM3
PreventionGenetics, part of Exact Sciences	RCV003407714	SCV004116182	likely pathogenic	RNU4ATAC-related disorder	2022-08-19	criteria provided, single submitter	clinical testing	The RNU4ATAC n.13C>T is a noncoding alteration. This variant has been reported in the compound heterozygous state with other noncoding variants in RNU4ATAC in patients with Roifman syndrome (Merico et al. 2015. PubMed ID: 26522830; Bogaert DJ et al 2017. PubMed ID: 28623346; Hallermayr A et al 2018. PubMed ID: 30455926; Wang LR et al 2020. PubMed ID: 32109076). Functional studies showed that this variant disrupts ncRNA function (Benoit-Pilven C et al 2020. PubMed ID: 32628740). This variant is reported in 0.059% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-122288468-C-T). This variant is interpreted as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202315	SCV005039932	pathogenic	Roifman syndrome	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: RNU4ATAC n.13C>T alters a conserved nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00035 in 129764 control chromosomes. n.13C>T has been reported in the literature in multiple individuals affected with Roifman Syndrome (example Merico_2015, Maddirevula_ 2018, Bhattad_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37898571, 29620724, 26522830). ClinVar contains an entry for this variant (Variation ID: 218083). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000202315	SCV005086388	pathogenic	Roifman syndrome	2022-09-02	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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephalic osteodysplastic primordial dwarfism, type I (MIM#210710), Roifman syndrome (MIM#616651), and Lowry-Wood syndrome (MIM#226960). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0217 - Non-coding variant with known effect. Transfected cells were proven to demonstrate significantly reduced splicing efficiencies (PMID: 32628740). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same position, is present in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0600 - Variant is located in the functionally important stem II region of the small nuclear RNA (PMID: 32628740). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in compound heterozygous individuals with Roifman syndrome (ClinVar, PMID: 32628740). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000202315	SCV000257314	pathogenic	Roifman syndrome	2015-11-02	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000202315	SCV001161807	likely pathogenic	Roifman syndrome		no assertion criteria provided	research
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000202315	SCV003807779	uncertain significance	Roifman syndrome	2022-11-22	flagged submission	clinical testing	ACMG classification criteria: PS3 supporting, PM3 moderated