NM_080632.3(UPF3B):c.674_677del (p.Arg225fs) AND Syndromic X-linked intellectual disability 14

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000012151.24

Allele description [Variation Report for NM_080632.3(UPF3B):c.674_677del (p.Arg225fs)]

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

Gene:

UPF3B:UPF3B regulator of nonsense mediated mRNA decay [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

Xq24

Genomic location:

Preferred name:

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

HGVS:

NC_000023.11:g.119841207TTCT[1]
NG_009241.1:g.16793GAAA[1]
NM_023010.4:c.674_677del
NM_080632.2:c.674_677delGAAA
NM_080632.3:c.674_677delMANE SELECT
NP_075386.1:p.Arg225fs
NP_542199.1:p.Arg225fs
NC_000023.10:g.118975169_118975172del
NC_000023.10:g.118975170TTCT[1]
NM_080632.1:c.674_677del
NM_080632.1:c.674_677delGAAA
NM_080632.2:c.674_677del
p.Arg225Lysfs*22

Protein change:

R225fs

Links:

OMIM: 300298.0001; dbSNP: rs794727881

NCBI 1000 Genomes Browser:

rs794727881

Molecular consequence:

NM_023010.4:c.674_677del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_080632.3:c.674_677del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Syndromic X-linked intellectual disability 14 (MRXS14)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 14
Identifiers:: MONDO: MONDO:0010398; MedGen: C1970822; Orphanet: 776; OMIM: 300676

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000032385	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17704778, 9805132
SCV001427222	Clinical Genomics Laboratory, Stanford Medicine	no assertion criteria provided	Pathogenic (Feb 10, 2020)	germline	clinical testing
SCV003445192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19238151, 17704778, 28492532
SCV003823824	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086114	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

FG syndrome: report of three new families with linkage to Xq12-q22.1.

Graham JM Jr, Tackels D, Dibbern K, Superneau D, Rogers C, Corning K, Schwartz CE.

Am J Med Genet. 1998 Nov 2;80(2):145-56.

PubMed [citation]

PMID:: 9805132

Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism.

Laumonnier F, Shoubridge C, Antar C, Nguyen LS, Van Esch H, Kleefstra T, Briault S, Fryns JP, Hamel B, Chelly J, Ropers HH, Ronce N, Blesson S, Moraine C, Gécz J, Raynaud M.

Mol Psychiatry. 2010 Jul;15(7):767-76. doi: 10.1038/mp.2009.14. Epub 2009 Feb 24.

PubMed [citation]

PMID:: 19238151

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000032385.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 brothers with X-linked syndromic intellectual developmental disorder-14 (MRXS14; 300676), Tarpey et al. (2007) identified a hemizygous 4-bp deletion (674delGAAA) in exon 7 of the UPF3B gene, resulting in a frameshift and premature termination of the protein. The family had originally been reported by Graham et al. (1998) as having Opitz-Kaveggia syndrome (305450). Clinical features included macrocephaly, long, thin face, widow's peak, upslanting palpebral fissures, long fingers, broad thumbs, and severe mental retardation associated with dysgenesis of the corpus callosum. Further studies showed that nonsense-mediated decay of mutant mRNA was only partially compromised.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genomics Laboratory, Stanford Medicine, SCV001427222.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	not provided

Description

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]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003445192.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003823824.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086114.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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