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

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jun 10, 2024
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:: RCV000006221.10

Allele description [Variation Report for NM_001113491.2(SEPTIN9):c.316C>T (p.Arg106Trp)]

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

Gene:

SEPTIN9:septin 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

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

HGVS:

NC_000017.11:g.77402298C>T
NG_011683.2:g.125889C>T
NM_001113491.2:c.316C>TMANE SELECT
NM_001113492.2:c.-177C>T
NM_001113493.2:c.295C>T
NM_001113494.1:c.-177C>T
NM_001293695.2:c.259C>T
NM_006640.5:c.262C>T
NP_001106963.1:p.Arg106Trp
NP_001106965.1:p.Arg99Trp
NP_001280624.1:p.Arg87Trp
NP_006631.2:p.Arg88Trp
NP_006631.2:p.Arg88Trp
LRG_370t1:c.262C>T
LRG_370t2:c.316C>T
LRG_370:g.125889C>T
LRG_370p1:p.Arg88Trp
LRG_370p2:p.Arg106Trp
NC_000017.10:g.75398380C>T
NG_011683.1:g.125889C>T
NM_001113491.1:c.316C>T
NM_006640.4:c.262C>T
p.ARG106TRP

Protein change:

R106W; ARG88TRP

Links:

OMIM: 604061.0001; dbSNP: rs80338761

NCBI 1000 Genomes Browser:

rs80338761

Molecular consequence:

NM_001113492.2:c.-177C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001113494.1:c.-177C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001113491.2:c.316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001113493.2:c.295C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293695.2:c.259C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006640.5:c.262C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Amyotrophic neuralgia
Synonyms:: Brachial plexus neuropathy, hereditary; Amyotrophy, hereditary neuralgic, with predilection for brachial plexus; Neuritis with brachial predilection; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008076; MedGen: C1834304; Orphanet: 2901; OMIM: 162100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026403	OMIM	no assertion criteria provided	Pathogenic (May 19, 2009)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 16186812, 18492087, 19451530
SCV000041183	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (3) [See all records that cite these PMIDs] 16186812, 18492087, 20301569
SCV000894152	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002075249	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV005043907	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005368240	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 10, 2024)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	paternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	phenotyping only
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy.

Hannibal MC, Ruzzo EK, Miller LR, Betz B, Buchan JG, Knutzen DM, Barnett K, Landsverk ML, Brice A, LeGuern E, Bedford HM, Worrall BB, Lovitt S, Appel SH, Andermann E, Bird TD, Chance PF.

Neurology. 2009 May 19;72(20):1755-9. doi: 10.1212/WNL.0b013e3181a609e3.

PubMed [citation]

PMID:: 19451530
PMCID:: PMC2683739

Mutations in SEPT9 cause hereditary neuralgic amyotrophy.

Kuhlenbäumer G, Hannibal MC, Nelis E, Schirmacher A, Verpoorten N, Meuleman J, Watts GD, De Vriendt E, Young P, Stögbauer F, Halfter H, Irobi J, Goossens D, Del-Favero J, Betz BG, Hor H, Kurlemann G, Bird TD, Airaksinen E, Mononen T, Serradell AP, Prats JM, et al.

Nat Genet. 2005 Oct;37(10):1044-6. Epub 2005 Sep 25.

PubMed [citation]

PMID:: 16186812

See all PubMed Citations (5)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000026403.3

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

Description

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.

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

From GeneReviews, SCV000041183.2

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

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

From Fulgent Genetics, Fulgent Genetics, SCV000894152.1

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

#	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 GenomeConnect, ClinGen, SCV002075249.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

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.

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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV005043907.1

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

Description

PS3_Moderate, PS4, PM2, PM6, PP3, PP1_Strong

#	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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV005368240.1

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

Description

Criteria applied: PS4,PS3_MOD,PP1_MOD,PS2_SUP,PM2_SUP

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

Last Updated: Oct 13, 2024

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