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NM_002180.3(IGHMBP2):c.1523C>T (p.Ser508Leu) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 17, 2023
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:
RCV001068853.8

Allele description [Variation Report for NM_002180.3(IGHMBP2):c.1523C>T (p.Ser508Leu)]

NM_002180.3(IGHMBP2):c.1523C>T (p.Ser508Leu)

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.1523C>T (p.Ser508Leu)
HGVS:
  • NC_000011.10:g.68933899C>T
  • NG_007976.1:g.35049C>T
  • NM_002180.3:c.1523C>TMANE SELECT
  • NP_002171.2:p.Ser508Leu
  • NP_002171.2:p.Ser508Leu
  • LRG_250t1:c.1523C>T
  • LRG_250:g.35049C>T
  • LRG_250p1:p.Ser508Leu
  • NC_000011.9:g.68701367C>T
  • NM_002180.2:c.1523C>T
Protein change:
S508L
Links:
dbSNP: rs754465226
NCBI 1000 Genomes Browser:
rs754465226
Molecular consequence:
  • NM_002180.3:c.1523C>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001233986Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jun 17, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies.

Karakaya M, Storbeck M, Strathmann EA, Delle Vedove A, Hölker I, Altmueller J, Naghiyeva L, Schmitz-Steinkrüger L, Vezyroglou K, Motameny S, Alawbathani S, Thiele H, Polat AI, Okur D, Boostani R, Karimiani EG, Wunderlich G, Ardicli D, Topaloglu H, Kirschner J, Schrank B, Maroofian R, et al.

Hum Mutat. 2018 Sep;39(9):1284-1298. doi: 10.1002/humu.23560. Epub 2018 Jul 25.

PubMed [citation]
PMID:
29858556

Clinical, electrophysiological and genetic characteristics of childhood hereditary polyneuropathies.

Paketci C, Karakaya M, Edem P, Bayram E, Keller N, Daimagüler HS, Cirak S, Jordanova A, Hiz S, Wirth B, Yiş U.

Rev Neurol (Paris). 2020 Dec;176(10):846-855. doi: 10.1016/j.neurol.2020.04.016. Epub 2020 Jul 21.

PubMed [citation]
PMID:
32709422
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001233986.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IGHMBP2 protein function. ClinVar contains an entry for this variant (Variation ID: 433162). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 29858556, 32709422; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 508 of the IGHMBP2 protein (p.Ser508Leu).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024