NM_003334.4(UBA1):c.1731C>T (p.Asn577=) AND Infantile-onset X-linked spinal muscular atrophy

Germline classification:: Pathogenic (3 submissions)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000010436.6

Allele description [Variation Report for NM_003334.4(UBA1):c.1731C>T (p.Asn577=)]

NM_003334.4(UBA1):c.1731C>T (p.Asn577=)

Gene:

UBA1:ubiquitin like modifier activating enzyme 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.3

Genomic location:

Preferred name:

NM_003334.4(UBA1):c.1731C>T (p.Asn577=)

HGVS:

NC_000023.11:g.47206103C>T
NG_009161.1:g.20304C>T
NG_021353.1:g.6256C>T
NM_003334.4:c.1731C>TMANE SELECT
NM_153280.3:c.1731C>T
NP_003325.2:p.Asn577=
NP_695012.1:p.Asn577=
NC_000023.10:g.47065502C>T
NM_003334.3:c.1731C>T

Protein change:

ASN577ASN

Links:

OMIM: 314370.0003; dbSNP: rs80356547

NCBI 1000 Genomes Browser:

rs80356547

Molecular consequence:

NM_003334.4:c.1731C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_153280.3:c.1731C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Infantile-onset X-linked spinal muscular atrophy
Synonyms:: ARTHROGRYPOSIS, X-LINKED, TYPE I; SPINAL MUSCULAR ATROPHY, X-LINKED LETHAL INFANTILE; Arthrogryposis multiplex congenita, distal, X-linked; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010532; MedGen: C1844934; Orphanet: 1145; OMIM: 301830

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000030662	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2008)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000041027	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 18179898, 20301739
SCV004046180	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000030662

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 2008)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000041027

GeneReviews

no classification provided

not provided

unknown

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV004046180

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

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	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.

Ramser J, Ahearn ME, Lenski C, Yariz KO, Hellebrand H, von Rhein M, Clark RD, Schmutzler RK, Lichtner P, Hoffman EP, Meindl A, Baumbach-Reardon L.

Am J Hum Genet. 2008 Jan;82(1):188-93. doi: 10.1016/j.ajhg.2007.09.009.

PubMed [citation]

PMID:: 18179898
PMCID:: PMC2253959

Spinal Muscular Atrophy, X-Linked Infantile.

Baumbach-Reardon L, Hunter JM, Ahearn ME, Pfautsch M.

2008 Oct 30 [updated 2024 May 9]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301739

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000030662.2

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

Description

In 3 families with infantile X-linked spinal muscular atrophy (SMAX2; 301830), Ramser et al. (2008) detected a novel synonymous C-to-T transition at nucleotide 1731 in exon 15 of the UBE1 gene. This substitution led to significant reduction of UBE1 expression and alteration of the methylation pattern of exon 15.

#	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 GeneReviews, SCV000041027.2

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

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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046180.1

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

Description

This synonymous variant has been previously reported as a hemizygous and de novo change in multiple unrelated males with X-linked spinal muscular atrophy (SMAX2) (MIM: #301830, PMID: 18179898, 26028276, 8528211). Analysis of blood cells from an affected individual harboring this variant demonstrated reduced UBA1 expression relative to healthy controls (PMID: 18179898). Bisulfite sequencing demonstrated that the c.1731C>T variant resulted in the loss of one CpG dinucleotide methylation site within a CpG island of 13 methylation sites located in exon 15 (PMID: 18179898). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1731C>T (p.Asn577Asn) variant is classified as Pathogenic.

#	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: May 1, 2024

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