Submissions for variant NM_080632.3(UPF3B):c.674_677del (p.Arg225fs)

dbSNP: rs794727881

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000494240	SCV000232325	pathogenic	not provided	2014-12-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000494240	SCV000583293	pathogenic	not provided	2022-02-02	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17704778, 26012578, 19377476, 24665081)
CeGaT Center for Human Genetics Tuebingen	RCV000494240	SCV001247900	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000012151	SCV003445192	pathogenic	Syndromic X-linked intellectual disability 14	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg225Lysfs*22) in the UPF3B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UPF3B are known to be pathogenic (PMID: 17704778, 19238151). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with UPF3B-related conditions (PMID: 17704778). It has also been observed to segregate with disease in related individuals. This variant is also known as 674_677delGAAA and/or R225fs*20. ClinVar contains an entry for this variant (Variation ID: 198608). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000012151	SCV003823824	pathogenic	Syndromic X-linked intellectual disability 14	2022-01-17	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012151	SCV005086114	pathogenic	Syndromic X-linked intellectual disability 14	2023-12-21	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 intellectual developmental disorder, X-linked syndromic 14 (MIM#300676). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000012151	SCV000032385	pathogenic	Syndromic X-linked intellectual disability 14	2007-09-01	no assertion criteria provided	literature only
Clinical Genomics Laboratory, Stanford Medicine	RCV000012151	SCV001427222	pathogenic	Syndromic X-linked intellectual disability 14	2020-02-10	no assertion criteria provided	clinical testing	The p.Arg225Lysfs*22 variant in the UPF3B gene has been reported de novo in 1 individual and maternally inherited in 4 additional unrelated individuals (GeneDx, personal communication, January 17, 2020; Tarpey et al., 2007). In one family the variant co-segregated with disease between siblings. All of these individuals were hemizygous males who presented features consistent with UPF3B-associated intellectual disability disorder. The p.Arg225Lysfs*22 variant results in a 4 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 22 amino acids downstream. Hemizygous loss of function is an established mechanism of disease for the UPF3B gene.The variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg225Lysfs*22 variant as pathogenic for X-linked UPF3B-associated intellectual disability disorder based on the information above. [ACMG evidence codes used: PVS1; PS2_supporting; PS4_supporting; PM2_supporting]
GenomeConnect, ClinGen	RCV001787090	SCV002029135	not provided	UPF3B-associated intellectual disability		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-10-2020 by Lab or GTR ID Stanford Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.