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NM_021830.5(TWNK):c.967C>T (p.Arg323Ter) AND Loeys-Dietz syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 20, 2024
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:
RCV004541262.1

Allele description [Variation Report for NM_021830.5(TWNK):c.967C>T (p.Arg323Ter)]

NM_021830.5(TWNK):c.967C>T (p.Arg323Ter)

Gene:
TWNK:twinkle mtDNA helicase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q24.31
Genomic location:
Preferred name:
NM_021830.5(TWNK):c.967C>T (p.Arg323Ter)
Other names:
p.R323*:CGA>TGA
HGVS:
  • NC_000010.11:g.100989177C>T
  • NG_011646.1:g.3339G>A
  • NG_012624.1:g.6642C>T
  • NM_001163812.2:c.967C>T
  • NM_001163813.2:c.-119-467C>T
  • NM_001163814.2:c.-119-467C>T
  • NM_001368275.1:c.-57-529C>T
  • NM_021830.5:c.967C>TMANE SELECT
  • NP_001157284.1:p.Arg323Ter
  • NP_068602.2:p.Arg323Ter
  • NC_000010.10:g.102748934C>T
  • NM_021830.4:c.967C>T
  • NR_160738.1:n.1635C>T
  • NR_160740.1:n.1635C>T
  • NR_160741.1:n.1635C>T
  • NR_160742.1:n.1635C>T
Protein change:
R323*
Links:
dbSNP: rs863223919
NCBI 1000 Genomes Browser:
rs863223919
Molecular consequence:
  • NM_001163813.2:c.-119-467C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001163814.2:c.-119-467C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001368275.1:c.-57-529C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NR_160738.1:n.1635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_160740.1:n.1635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_160741.1:n.1635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_160742.1:n.1635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_001163812.2:c.967C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_021830.5:c.967C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Loeys-Dietz syndrome (LDS)
Identifiers:
MONDO: MONDO:0018954; MedGen: C2697932; OMIM: PS609192

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005040837Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Mar 20, 2024) 		germlineclinical testing

Citation Link

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Summary from all submissions

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

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005040837.1

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

Description

Variant summary: SMAD3 c.967C>T (p.Arg323Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.967C>T in individuals affected with Loeys-Dietz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (FBN1 c.5885A>G, p.Tyr1962Cys), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Jun 23, 2024