VCV000005863.21 - ClinVar

NM_001113491.2(SEPTIN9):c.316C>T (p.Arg106Trp)

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.

(12)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001113491.2(SEPTIN9):c.316C>T (p.Arg106Trp)

Variation ID: 5863 Accession: VCV000005863.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q25.3 17: 77402298 (GRCh38) [ NCBI UCSC ] 17: 75398380 (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	Apr 4, 2013	Oct 13, 2024	Jun 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001113491.2:c.316C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001106963.1:p.Arg106Trp	missense
NM_006640.5:c.262C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006631.2:p.Arg88Trp	missense
NM_001113492.2:c.-177C>T		5 prime UTR
NM_001113493.2:c.295C>T	NP_001106965.1:p.Arg99Trp	missense
NM_001113494.1:c.-177C>T		5 prime UTR
NM_001293695.2:c.259C>T	NP_001280624.1:p.Arg87Trp	missense
NC_000017.11:g.77402298C>T
NC_000017.10:g.75398380C>T
NG_011683.2:g.125889C>T
LRG_370:g.125889C>T
LRG_370t1:c.262C>T	LRG_370p1:p.Arg88Trp
LRG_370t2:c.316C>T	LRG_370p2:p.Arg106Trp

... more HGVS ... less HGVS

Protein change

R88W, R106W, R99W, R87W

Other names

Canonical SPDI

NC_000017.11:77402297: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA340468 OMIM: 604061.0001 dbSNP: rs80338761 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.
SEPTIN9		-	-	GRCh38 GRCh38 GRCh37	636	673

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.
Amyotrophic neuralgia	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jun 10, 2024	RCV000006221.10
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 17, 2023	RCV000516514.14
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2022	RCV004018574.2

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.
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amyotrophic neuralgia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894152.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (May 17, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001873548.4 First in ClinVar: Sep 19, 2021 Last updated: May 27, 2023	Comment: Published functional studies demonstrate a damaging effect resulting in likely altered interactions with partner molecules and lack of response to Rhotekin signaling (Sudo et al., … (more) Published functional studies demonstrate a damaging effect resulting in likely altered interactions with partner molecules and lack of response to Rhotekin signaling (Sudo et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19451530, 16186812, 30019529, 31619932, 18492087, 19204161, 20019224, 22981636, 27535533, 17546647, 28503616) (less)
Pathogenic (Dec 13, 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: SCV004947200.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (9) PubMed: 16186812‚ 17546647‚ 18492087‚ 19204161‚ 19451530‚ 20019224‚ 22981636‚ 28503616‚ 31619932 Comment: The c.262C>T (p.R88W) alteration is located in coding exon 2 of the SEPT9 gene. This alteration results from a C to T substitution at nucleotide … (more) The c.262C>T (p.R88W) alteration is located in coding exon 2 of the SEPT9 gene. This alteration results from a C to T substitution at nucleotide position 262, causing the arginine (R) at amino acid position 88 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple families with hereditary neuralgic amyotrophy (Kuhlenbäumer, 2005; Laccone, 2008; Hannibal, 2009; Klein, 2009; Ueda, 2010; Leshinsky-Silver, 2013; Chuk, 2016; Serin, 2019). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.R88W alteration alters the interaction of septin-9 with partner molecules (Sudo, 2007). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Aug 23, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000612193.2 First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2021	Publications: PubMed (7) PubMed: 17546647‚ 20019224‚ 16186812‚ 18492087‚ 19451530‚ 19204161‚ 22981636 Comment: Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. … (more) Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. (less)
Pathogenic (May 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002510800.3 First in ClinVar: May 16, 2022 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 17546647‚ 16186812‚ 18492087‚ 19204161‚ 20019224‚ 22981636‚ 28503616‚ 31619932 Comment: 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) … (more) 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 SEPT9 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SEPT9 function (PMID: 17546647). ClinVar contains an entry for this variant (Variation ID: 5863). This missense change has been observed in individual(s) with hereditary neuralgic amyotrophy (PMID: 16186812, 18492087, 19204161, 20019224, 22981636, 28503616, 31619932). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 88 of the SEPT9 protein (p.Arg88Trp). (less)
Pathogenic (Mar 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amyotrophic neuralgia Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV005043907.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Comment: PS3_Moderate, PS4, PM2, PM6, PP3, PP1_Strong
Pathogenic (Jun 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Amyotrophic neuralgia (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368240.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PS4,PS3_MOD,PP1_MOD,PS2_SUP,PM2_SUP Clinical Features: Upper limb amyotrophy (present) , Increased circulating lipoprotein lipase concentration (present) , Cavernous hemangioma (present) Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001966839.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (May 19, 2009)	no assertion criteria provided Method: literature only	AMYOTROPHY, HEREDITARY NEURALGIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026403.3 First in ClinVar: Apr 04, 2013 Last updated: May 07, 2024	Publications: PubMed (3) PubMed: 16186812‚ 18492087‚ 19451530 Comment on evidence: In 4 families of different geographic origins, Kuhlenbaumer et al. (2005) found that hereditary neuralgic amyotrophy (HNA; 162100) was associated with a heterozygous 262C-T transition … (more) In 4 families of different geographic origins, Kuhlenbaumer et al. (2005) found that hereditary neuralgic amyotrophy (HNA; 162100) was associated with a heterozygous 262C-T transition in exon 2 of the SEPT9 gene, resulting in an arg88-to-trp (R88W) amino acid change. The 4 families did not share a common disease-associated haplotype, suggestive of a mutation hotspot rather than a founder mutation. Genomic variation occurred at a potential hypermutable CG dinucleotide. One of the 4 families was North American of European descent, 2 were Spanish, and 1 was Finnish. Dysmorphic features were present in affected members of each of the 4 families. Laccone et al. (2008) identified heterozygosity for the R88W mutation in 4 affected members of a 3-generation family with HNA. Two sibs had dysmorphic features as children, including hypotelorism, upslanting palpebral fissures, deep-set eyes, blepharophimosis, and epicanthal folds. Developmental milestones were normal. On history, the father and paternal grandmother reported painful episodes of brachial muscle weakness with residual wasting and paralysis, consistent with HNA. Photographs of the father and grandmother as children showed similar dysmorphic features as in the 2 sibs. Both sibs also developed brachial neuritis. Hannibal et al. (2009) identified the R88W mutation in affected members of 7 of 42 unrelated pedigrees with HNA. Haplotype analysis indicated a founder effect. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921335.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
not provided (-)	no classification provided Method: literature only	Amyotrophic neuralgia Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000041183.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 16186812‚ 18492087‚ 20301569 BookShelf: NBK1395 BookShelf: NBK1395
not provided (-)	no classification provided Method: phenotyping only	Amyotrophic neuralgia Affected status: yes Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002075249.2 First in ClinVar: Feb 11, 2022 Last updated: Jan 07, 2023	Comment: Variant classified as Pathogenic and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant classified as Pathogenic and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Short stature (present) , Abnormality of vision (present) , Myopia (present) , Sensorineural hearing loss disorder (present) , Tinnitus (present) , Abnormality of coordination (present) … (more) Short stature (present) , Abnormality of vision (present) , Myopia (present) , Sensorineural hearing loss disorder (present) , Tinnitus (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Movement disorder (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Abnormal muscle physiology (present) , Abnormal skeletal muscle morphology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormal morphology of the pelvis musculature (present) , Cardiac arrhythmia (present) , Abnormal cardiovascular system morphology (present) (less) Indication for testing: Diagnostic Age: 50-59 years Sex: male Method: Gene Panel Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2021-07-21 Testing laboratory interpretation: Pathogenic
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Comment:

Published functional studies demonstrate a damaging effect resulting in likely altered interactions with partner molecules and lack of response to Rhotekin signaling (Sudo et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19451530, 16186812, 30019529, 31619932, 18492087, 19204161, 20019224, 22981636, 27535533, 17546647, 28503616)

Comment:

The c.262C>T (p.R88W) alteration is located in coding exon 2 of the SEPT9 gene. This alteration results from a C to T substitution at nucleotide position 262, causing the arginine (R) at amino acid position 88 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple families with hereditary neuralgic amyotrophy (Kuhlenbäumer, 2005; Laccone, 2008; Hannibal, 2009; Klein, 2009; Ueda, 2010; Leshinsky-Silver, 2013; Chuk, 2016; Serin, 2019). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.R88W alteration alters the interaction of septin-9 with partner molecules (Sudo, 2007). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.

Comment:

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 SEPT9 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SEPT9 function (PMID: 17546647). ClinVar contains an entry for this variant (Variation ID: 5863). This missense change has been observed in individual(s) with hereditary neuralgic amyotrophy (PMID: 16186812, 18492087, 19204161, 20019224, 22981636, 28503616, 31619932). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 88 of the SEPT9 protein (p.Arg88Trp).

Comment:

Variant classified as Pathogenic and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
A rare cause of brachial plexopathy: hereditary neuralgic amyotrophy.	Serin HM	Turk pediatri arsivi	2019	PMID: 31619932
Pediatric Hereditary Neuralgic Amyotrophy: Successful Treatment With Intravenous Immunoglobulin and Insights Into SEPT9 Pathogenesis.	Chuk R	Child neurology open	2016	PMID: 28503616
Neonatal vocal cord paralysis-an early presentation of hereditary neuralgic amyotrophy due to a mutation in the SEPT9 gene.	Leshinsky-Silver E	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2013	PMID: 22981636
Hereditary Neuralgic Amyotrophy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2012	PMID: 20301569
Phenotypic spectrum of hereditary neuralgic amyotrophy caused by the SEPT9 R88W mutation.	Ueda M	Journal of neurology, neurosurgery, and psychiatry	2010	PMID: 20019224
SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy.	Hannibal MC	Neurology	2009	PMID: 19451530
SEPT9 mutations and a conserved 17q25 sequence in sporadic and hereditary brachial plexus neuropathy.	Klein CJ	Archives of neurology	2009	PMID: 19204161
Dysmorphic syndrome of hereditary neuralgic amyotrophy associated with a SEPT9 gene mutation--a family study.	Laccone F	Clinical genetics	2008	PMID: 18492087
SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling.	Sudo K	Human mutation	2007	PMID: 17546647
Mutations in SEPT9 cause hereditary neuralgic amyotrophy.	Kuhlenbäumer G	Nature genetics	2005	PMID: 16186812

Text-mined citations for rs80338761 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_001113491.2(SEPTIN9):c.316C>T (p.Arg106Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338761 ...