VCV001015530.8 - ClinVar

NM_002180.3(IGHMBP2):c.2188C>T (p.Arg730Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002180.3(IGHMBP2):c.2188C>T (p.Arg730Trp)

Variation ID: 1015530 Accession: VCV001015530.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.3 11: 68936668 (GRCh38) [ NCBI UCSC ] 11: 68704136 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 14, 2021	May 1, 2024	Apr 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002180.3:c.2188C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002171.2:p.Arg730Trp	missense
NC_000011.10:g.68936668C>T
NC_000011.9:g.68704136C>T
NG_007976.1:g.37818C>T
LRG_250:g.37818C>T
LRG_250t1:c.2188C>T

... more HGVS ... less HGVS

Protein change

R730W

Other names

Canonical SPDI

NC_000011.10:68936667:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00003

Exome Aggregation Consortium (ExAC) 0.00006

The Genome Aggregation Database (gnomAD) 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00009

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

dbSNP: rs146409569 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
IGHMBP2		-	-	GRCh38 GRCh37	1337	1417

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal recessive distal spinal muscular atrophy 1 Charcot-Marie-Tooth disease axonal type 2S	Uncertain significance (1)	criteria provided, single submitter	Jul 6, 2022	RCV001314406.4
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Sep 8, 2022	RCV002431891.2
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 27, 2023	RCV003130260.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jul 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive distal spinal muscular atrophy 1 Charcot-Marie-Tooth disease axonal type 2S Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001504939.3 First in ClinVar: Mar 14, 2021 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 33369814 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 730 of the IGHMBP2 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 730 of the IGHMBP2 protein (p.Arg730Trp). This variant is present in population databases (rs146409569, gnomAD 0.01%). This missense change has been observed in individual(s) with distal hereditary motor neuropathy (PMID: 33369814). ClinVar contains an entry for this variant (Variation ID: 1015530). 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 not expected to disrupt IGHMBP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 08, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002730169.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 33369814 Comment: The p.R730W variant (also known as c.2188C>T), located in coding exon 13 of the IGHMBP2 gene, results from a C to T substitution at nucleotide … (more) The p.R730W variant (also known as c.2188C>T), located in coding exon 13 of the IGHMBP2 gene, results from a C to T substitution at nucleotide position 2188. The arginine at codon 730 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected in an individual with childhood-onset distal hereditary motor neuropathy; however,a second allele in IGHMPB2 was not described (Frasquet M et al. Eur J Neurol, 2021 04;28:1334-1343). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Apr 27, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003923862.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Comment: Observed as heterozygous variant and with another variant in patients with distal motor neuropathy in published literature (Frasquet et al., 2020; Yang et al., 2022); … (more) Observed as heterozygous variant and with another variant in patients with distal motor neuropathy in published literature (Frasquet et al., 2020; Yang et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: Yang2022[Abstract], 33369814) (less)
Uncertain significance (Jul 11, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003813306.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 730 of the IGHMBP2 protein (p.Arg730Trp). This variant is present in population databases (rs146409569, gnomAD 0.01%). This missense change has been observed in individual(s) with distal hereditary motor neuropathy (PMID: 33369814). ClinVar contains an entry for this variant (Variation ID: 1015530). 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 not expected to disrupt IGHMBP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.R730W variant (also known as c.2188C>T), located in coding exon 13 of the IGHMBP2 gene, results from a C to T substitution at nucleotide position 2188. The arginine at codon 730 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected in an individual with childhood-onset distal hereditary motor neuropathy; however,a second allele in IGHMPB2 was not described (Frasquet M et al. Eur J Neurol, 2021 04;28:1334-1343). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Observed as heterozygous variant and with another variant in patients with distal motor neuropathy in published literature (Frasquet et al., 2020; Yang et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: Yang2022[Abstract], 33369814)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation.	Frasquet M	European journal of neurology	2021	PMID: 33369814

Text-mined citations for rs146409569 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002180.3(IGHMBP2):c.2188C>T (p.Arg730Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146409569 ...