Submissions for variant NM_001110792.2(MECP2):c.1122dup (p.Lys375fs)

dbSNP: rs587783092

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000284365	SCV000330465	pathogenic	not provided	2016-04-26	criteria provided, single submitter	clinical testing	The de novo c.1086dupC pathogenic variant in the MECP2 gene has not been reported previously asa pathogenic variant nor as a benign variant, to our knowledge. The c.1086dupC variant causes aframeshift starting with codon Lysine 363, changes this amino acid to a Glutamine residue, and createsa premature Stop codon at position 30 of the new reading frame, denoted p.Lys363GlnfsX30. Thisvariant is predicted to cause loss of normal protein function through protein truncation. Furthermore,the c.1086dupC variant was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. Therefore, we interpret c.1086dupC as a pathogenic variant.
Invitae	RCV001207928	SCV001379296	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2022-12-02	criteria provided, single submitter	clinical testing	This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (PMID: 17089071, 17387578, 19914908, 20151026, 21982064). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 280541). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys363Glnfs*30) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 124 amino acid(s) of the MECP2 protein. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000284365	SCV002017244	pathogenic	not provided	2019-03-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429211	SCV002730795	pathogenic	Inborn genetic diseases	2019-10-28	criteria provided, single submitter	clinical testing	The c.1086dupC pathogenic mutation, located in coding exon 3 of the MECP2 gene, results from a duplication of C at nucleotide position 1086, causing a translational frameshift with a predicted alternate stop codon (p.K363Qfs*30). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470836	SCV002767202	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2020-10-19	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: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0110 - This gene is known to be predominantly associated with X-linked dominant disease. However, X-linked recessive disease has also been reported. In addition, both random and skewed inactivation have been seen in females (OMIM), the latter usually present a milder phenotype or no symptoms (PMID: 20301670). (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected. (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Several truncating variants located downstream have been reported pathogenic (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has reported to be de novo in a single patient (ClinVar). (P) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Diagnostic Laboratory, Strasbourg University Hospital	RCV002274968	SCV002562822	pathogenic	Seizure		no assertion criteria provided	clinical testing