Submissions for variant NM_002430.3(MN1):c.3883C>T (p.Arg1295Ter)

dbSNP: rs147334255

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190793	SCV000244234	pathogenic	Inborn genetic diseases	2022-09-02	criteria provided, single submitter	clinical testing	The c.3883C>T (p.R1295*) alteration, located in exon 2 of the MN1 gene, results from a C to T substitution at nucleotide position 3883. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1295. This alteration occurs at the 3' terminus of the MN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and this alteration and similar truncating alterations have been reported in the literature as disease-causing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with MN1 C-terminal deletion syndrome (Mak, 2020; Miyake, 2020, DECIPHER v.9.32, Ambry internal data). Functional analysis demonstrated protein that contain the p.R1295* alteration is still expressed but with a predicted absence of the C-terminal region. Protein without the C-terminal region showed increased stability and aggregation, as well as an inhibitory effect on cell proliferation compared to wild type. Additionally, transcriptome analysis of lymphoblastoid cell lines from a heterozygous patient suggested abnormal transcriptional regulation of multiple genes (Miyake, 2020). Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000413400	SCV000491051	uncertain significance	not specified	2016-12-02	criteria provided, single submitter	clinical testing	The R1295X variant in the MN1 gene has been reported previously as a de novo finding identified via whole exome sequencing in a single patient with generalized epilepsy (Helbig et al., 2016). This variant is predicted to cause loss of normal protein function through protein truncation. The R1295X variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R1295X as a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000726804	SCV000703181	uncertain significance	not provided	2016-10-31	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV001003395	SCV001432977	pathogenic	CEBALID syndrome	2020-07-29	criteria provided, single submitter	curation	This variant is interpreted as Pathogenic for CEBALID syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants (PM4); De novo (paternity and maternity confirmed) (PS2 upgraded to very strong); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to moderate).
CeGaT Center for Human Genetics Tuebingen	RCV000726804	SCV001501834	likely pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001003395	SCV002768040	pathogenic	CEBALID syndrome	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 2 of 2). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. The C-terminus is responsible for protein degradation (PMID: 31839203). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Three truncating variants have been reported downstream from this variant (PMID: 31834374). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported to be de novo in nine patients with CEBALID syndrome (PMID: 31834374, 31839203). (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Baylor Genetics	RCV001003395	SCV003834989	pathogenic	CEBALID syndrome	2021-02-01	criteria provided, single submitter	clinical testing
OMIM	RCV001003395	SCV001161682	pathogenic	CEBALID syndrome	2020-02-14	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV001258025	SCV001434839	likely pathogenic	MN1 C-terminal truncation (MCTT) syndrome		no assertion criteria provided	research
GeneReviews	RCV001003395	SCV001469062	not provided	CEBALID syndrome		no assertion provided	literature only	Recurrent pathogenic variant in 9 out of 25 persons