NM_012431.3(SEMA3E):c.1855C>T (p.Arg619Cys) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Oct 15, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000207418.2

Allele description [Variation Report for NM_012431.3(SEMA3E):c.1855C>T (p.Arg619Cys)]

NM_012431.3(SEMA3E):c.1855C>T (p.Arg619Cys)

Gene:
SEMA3E:semaphorin 3E [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7q21.11
Genomic location:
Preferred name:
NM_012431.3(SEMA3E):c.1855C>T (p.Arg619Cys)
HGVS:
  • NC_000007.14:g.83385314G>A
  • NG_021242.2:g.268850C>T
  • NM_001178129.2:c.1675C>T
  • NM_012431.3:c.1855C>TMANE SELECT
  • NP_001171600.1:p.Arg559Cys
  • NP_036563.1:p.Arg619Cys
  • LRG_1287t1:c.1855C>T
  • LRG_1287:g.268850C>T
  • LRG_1287p1:p.Arg619Cys
  • NC_000007.13:g.83014630G>A
  • NM_012431.2:c.1855C>T
Protein change:
R559C; ARG619CYS
Links:
OMIM: 608166.0002; dbSNP: rs143631464
NCBI 1000 Genomes Browser:
rs143631464
Molecular consequence:
  • NM_001178129.2:c.1675C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012431.3:c.1855C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000262695OMIMno assertion criteria providedUncertain significance
(Feb 9, 2016)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV002005128GeneDxcriteria provided, single submitter
Uncertain significance
(Oct 15, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome.

Cariboni A, André V, Chauvet S, Cassatella D, Davidson K, Caramello A, Fantin A, Bouloux P, Mann F, Ruhrberg C.

J Clin Invest. 2015 Jun;125(6):2413-28. doi: 10.1172/JCI78448. Epub 2015 May 18.

PubMed [citation]
PMID:
25985275
PMCID:
PMC4497752

Details of each submission

From OMIM, SCV000262695.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

This variant is classified as a variant of unknown significance because its contribution to hypogonadotropic hypogonadism with anosmia (Kallmann syndrome; see 147950) has not been confirmed.

Cariboni et al. (2015) performed exome sequencing in 121 patients with Kallmann syndrome and identified 2 affected brothers with heterozygosity for a c.1855C-T transition (c.1855C-T, ENST00000307792.3) in exon 16 of the SEMA3E gene, resulting in an arg619-to-cys (R619C) substitution at a residue that is highly conserved in mammals. Analysis of their exome data for mutation in known Kallmann syndrome-associated genes revealed that both brothers were also heterozygous for an F1019C substitution in the hypogonadotropic hypogonadism-5 (HH5; 612370)-associated CHD7 gene (608892). Parental DNA was unavailable for study. The brothers were diagnosed at ages 15 and 17 years, respectively, with anosmia, prepubertal testes, and GnRH deficiency in the setting of hypogonadal testosterone levels. The SEMA3E mutation was not found in the 1000 Genomes Project database, and occurred at a very low minor allele frequency (0.0004%) in the NHLBI GO Exome Sequencing Project database in European ancestry samples, whereas the CHD7 mutation was not found in either database. Ligand-binding assays demonstrated that both wildtype SEMA3E and the R619C mutant bound GT1-7 cells (maturing hypothalamic GnRH neurons, see 152760), although the mutant failed to protect the cells from serum starvation-induced death. In addition, the mutant was ineffective in AKT (164730) activation in serum-starved GT1-7 cells. Cariboni et al. (2015) suggested that SEMA3E-mediated survival signaling in maturing GnRH neurons is compromised by the R619C mutation.

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

From GeneDx, SCV002005128.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Observed in siblings with Kallman syndrome who were also heterozygous for a variant in the CHD7 gene and observed in a patient with CHARGE syndrome whose unaffected parent was also heterozygous (Cariboni et al., 2015; Lalani et al., 2004); Published in vitro functional studies demonstrate a damaging effect on protein function (Cariboni et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25985275, 29144511, 15235037)

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

Last Updated: Nov 27, 2021

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