NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter) AND Autosomal recessive distal spinal muscular atrophy 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 2, 2022
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:: RCV000235082.8

Allele description [Variation Report for NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter)]

NM_002180.3(IGHMBP2):c.1488C>A (p.Cys496Ter)

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.1488C>A (p.Cys496Ter)

HGVS:

NC_000011.10:g.68933864C>A
NG_007976.1:g.35014C>A
NM_002180.3:c.1488C>AMANE SELECT
NP_002171.2:p.Cys496Ter
NP_002171.2:p.Cys496Ter
LRG_250t1:c.1488C>A
LRG_250:g.35014C>A
LRG_250p1:p.Cys496Ter
NC_000011.9:g.68701332C>A
NM_002180.2:c.1488C>A
p.Cys496*

Protein change:

C496*

Links:

dbSNP: rs145226920

NCBI 1000 Genomes Browser:

rs145226920

Molecular consequence:

NM_002180.3:c.1488C>A - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000292359	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	criteria provided, single submitter (Pitt et al. (Brain 2003))	Pathogenic (Aug 18, 2015)	maternal	research	PubMed (4) [See all records that cite these PMIDs] 14506069, 23806086, 24088041, 26257172
SCV001138369	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001245043	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25439726, 30598237, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000292359

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

criteria provided, single submitter

(Pitt et al. (Brain 2003))

Pathogenic
(Aug 18, 2015)

maternal

research

PubMed (4)
[See all records that cite these PMIDs]

SCV001138369

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Pathogenic
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV001245043

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 2, 2022)

germline

clinical testing

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	1	1	not provided	not provided	not provided	research

Citations

PubMed

Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1.

Pitt M, Houlden H, Jacobs J, Mok Q, Harding B, Reilly M, Surtees R.

Brain. 2003 Dec;126(Pt 12):2682-92. Epub 2003 Sep 23.

PubMed [citation]

PMID:: 14506069

Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy.

Lupski JR, Gonzaga-Jauregui C, Yang Y, Bainbridge MN, Jhangiani S, Buhay CJ, Kovar CL, Wang M, Hawes AC, Reid JG, Eng C, Muzny DM, Gibbs RA.

Genome Med. 2013;5(6):57. doi: 10.1186/gm461.

PubMed [citation]

PMID:: 23806086
PMCID:: PMC3706849

See all PubMed Citations (7)

Details of each submission

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000292359.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (4)

Description

This variant has been previously reported as disease-causing and was identified in trans with a predicted pathogenic variant in an individual with congenital hypotonia.

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

From Mendelics, SCV001138369.1

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

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001245043.3

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

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 Charcot-Marie-Tooth disease, axonal, type 2S (MIM#616155), and distal hereditary motor neuronopathy, type VI (MIM#604320). (I) 0106 - This gene is associated with autosomal 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) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (42 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic in individuals with either spinal muscular atrophy with respiratory distress (SMARD) or Charcot-Marie-Tooth (CMT) (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both compound heterozygous and homozygous individuals with SMARD, and rarely in individuals with CMT (ClinVar, PMID: 25439726, PMID: 30598237). (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: May 7, 2024

ClinVar

Relating variation to medicine