NM_005068.2(SIM1):c.2123A>G (p.Lys708Arg) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: May 17, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000478425.1

Allele description

NM_005068.2(SIM1):c.2123A>G (p.Lys708Arg)

Gene:
SIM1:SIM bHLH transcription factor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6q16.3
Genomic location:
Preferred name:
NM_005068.2(SIM1):c.2123A>G (p.Lys708Arg)
HGVS:
  • NC_000006.12:g.100390539T>C
  • NG_008230.1:g.78137A>G
  • NM_005068.2:c.2123A>G
  • NP_005059.2:p.Lys708Arg
  • NC_000006.11:g.100838415T>C
Protein change:
K708R
Links:
dbSNP: rs1064795024
NCBI 1000 Genomes Browser:
rs1064795024
Molecular consequence:
  • NM_005068.2:c.2123A>G - 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
SCV000570416GeneDxcriteria provided, single submitter
Likely pathogenic
(May 17, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000570416.3

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

Description

The K708R variant in the SIM1 gene has not been reported previously as a pathogenic variant, nor asa benign variant, to our knowledge. The K708R variant was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The K708R variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. This substitution occurs at a position where amino acids withsimilar properties to Lysine are tolerated across species. In silico analysis is inconsistent in itspredictions as to whether or not the variant is damaging to the protein structure/function. Missensevariants in nearby residues (D707H and T712I) have been reported in patients with obesity andautonomic nervous system dysfunction (Ramachandrappa et al., 2013), supporting the functionalimportance of this region of the protein. The K708R variant is a strong candidate for a pathogenicvariant, however the possibility it may be a rare benign variant cannot be excluded.

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

Last Updated: Sep 8, 2018