NM_002180.3(IGHMBP2):c.1477A>G (p.Thr493Ala) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 15, 2022
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:: RCV001929258.6

Allele description [Variation Report for NM_002180.3(IGHMBP2):c.1477A>G (p.Thr493Ala)]

NM_002180.3(IGHMBP2):c.1477A>G (p.Thr493Ala)

Gene:

IGHMBP2:immunoglobulin mu DNA binding protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.3

Genomic location:

Preferred name:

NM_002180.3(IGHMBP2):c.1477A>G (p.Thr493Ala)

HGVS:

NC_000011.10:g.68933853A>G
NG_007976.1:g.35003A>G
NM_002180.3:c.1477A>GMANE SELECT
NP_002171.2:p.Thr493Ala
LRG_250:g.35003A>G
NC_000011.9:g.68701321A>G

Protein change:

T493A

Links:

dbSNP: rs2154008651

NCBI 1000 Genomes Browser:

rs2154008651

Molecular consequence:

NM_002180.3:c.1477A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive distal spinal muscular atrophy 1
Synonyms:: HMN VI; SPINAL MUSCULAR ATROPHY, DIAPHRAGMATIC; Spinal muscular atrophy with respiratory distress 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011436; MedGen: C1858517; Orphanet: 98920; OMIM: 604320

Name:: Charcot-Marie-Tooth disease axonal type 2S
Synonyms:: CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2S; CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2S
Identifiers:: MONDO: MONDO:0014511; MedGen: C4015349; Orphanet: 443073; OMIM: 616155

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002206813	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18802676, 19157874, 25454169, 27450922, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002206813

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 15, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease.

Guenther UP, Handoko L, Varon R, Stephani U, Tsao CY, Mendell JR, Lützkendorf S, Hübner C, von Au K, Jablonka S, Dittmar G, Heinemann U, Schuetz A, Schuelke M.

J Mol Med (Berl). 2009 Jan;87(1):31-41. doi: 10.1007/s00109-008-0402-7. Epub 2008 Sep 18.

PubMed [citation]

PMID:: 18802676

Interfamilial phenotypic heterogeneity in SMARD1.

Joseph S, Robb SA, Mohammed S, Lillis S, Simonds A, Manzur AY, Walter S, Wraige E.

Neuromuscul Disord. 2009 Mar;19(3):193-5. doi: 10.1016/j.nmd.2008.11.013. Epub 2009 Jan 20.

PubMed [citation]

PMID:: 19157874

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002206813.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 493 of the IGHMBP2 protein (p.Thr493Ala). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr493 amino acid residue in IGHMBP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18802676, 19157874, 25454169, 27450922). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IGHMBP2 protein function. This missense change has been observed in individual(s) with clinical features of spinal muscular atrophy with respiratory distress (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency).

#	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

Last Updated: Sep 29, 2024

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