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NM_020796.5(SEMA6A):c.1268T>C (p.Ile423Thr) AND Delayed puberty, self-limited

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 5, 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:
RCV003312987.1

Allele description [Variation Report for NM_020796.5(SEMA6A):c.1268T>C (p.Ile423Thr)]

NM_020796.5(SEMA6A):c.1268T>C (p.Ile423Thr)

Gene:
SEMA6A:semaphorin 6A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q23.1
Genomic location:
Preferred name:
NM_020796.5(SEMA6A):c.1268T>C (p.Ile423Thr)
HGVS:
  • NC_000005.10:g.116478701A>G
  • NM_001300780.2:c.1268T>C
  • NM_020796.5:c.1268T>CMANE SELECT
  • NP_001287709.1:p.Ile423Thr
  • NP_065847.1:p.Ile423Thr
  • NC_000005.9:g.115814397A>G
Protein change:
I423T
Molecular consequence:
  • NM_001300780.2:c.1268T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020796.5:c.1268T>C - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
effect on protein subcellular localization [Variation Ontology: 0033]

Condition(s)

Name:
Delayed puberty, self-limited
Synonyms:
CONSTITUTIONAL DELAY OF PUBERTY
Identifiers:
MONDO: MONDO:0859205; MedGen: C2874202; OMIM: 619613

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003936134Centre for Endocrinology, Queen Mary University of London
criteria provided, single submitter

(Submitter's publication)		Likely pathogenic
(Jul 5, 2023) 		inherited, not applicableresearch

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providednot applicablenot applicablenot providednot providednot providednot providednot providedresearch
Finnishinheritedyes63not providednot providednot providedresearch

Details of each submission

From Centre for Endocrinology, Queen Mary University of London, SCV003936134.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
2Finnish6not providednot providedresearchnot provided

Description

The in vitro results strongly support our in silico predictions and indicate that the I423T variant might affect SEMA6A stability and impair intracellular protein trafficking. The consequent defective membrane localization would hamper any paracellular interaction with SEMA6A receptors, suggesting a loss-of-function effect of the SEMA6AI423T variant in patients.

Description

The Ile423Thr variant has been reported in 3 Finnish families with autosomal dominant self-limited delayed puberty segregating with disease in 4 affected relatives (Lettieri 2023 in review Nat Comm) and is absent from large population studies. Additionally, in vitro functional studies indicate that the Ile423Thr variant disrupts protein stability and subcellular localisation (Lettieri 2023 in review Nat Comm). Thus, the Ile423Thr variant meets our criteria to be classified as pathogenic based upon segregation, absence from controls and functional evidence.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not applicablenot applicablenot providednot providednot providednot providednot providednot providednot provided
2inheritedyesnot providednot providednot provided6not provided3not provided

Last Updated: Aug 26, 2023