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NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp) AND RASopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 11, 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:
RCV004545219.1

Allele description [Variation Report for NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp)]

NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp)

Gene:
DDC:dopa decarboxylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p12.2
Genomic location:
Preferred name:
NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp)
HGVS:
  • NC_000007.14:g.50467222G>A
  • NG_008742.1:g.103235C>T
  • NM_000790.3:c.1234C>T
  • NM_000790.4:c.1234C>T
  • NM_001082971.2:c.1234C>TMANE SELECT
  • NM_001242886.2:c.1120C>T
  • NM_001242887.2:c.1090C>T
  • NM_001242888.2:c.1000C>T
  • NM_001242889.2:c.955C>T
  • NP_000781.2:p.Arg412Trp
  • NP_001076440.2:p.Arg412Trp
  • NP_001229815.2:p.Arg374Trp
  • NP_001229816.2:p.Arg364Trp
  • NP_001229817.2:p.Arg334Trp
  • NP_001229818.2:p.Arg319Trp
  • NC_000007.13:g.50534920G>A
  • NM_000790.4:c.1234C>T
Protein change:
R319W
Links:
dbSNP: rs542063660
NCBI 1000 Genomes Browser:
rs542063660
Molecular consequence:
  • NM_000790.4:c.1234C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001082971.2:c.1234C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242886.2:c.1120C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242887.2:c.1090C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242888.2:c.1000C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242889.2:c.955C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
RASopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: C5555857

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV005040793Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Mar 11, 2024)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency: from molecular mechanisms to therapy implications.

Montioli R, Dindo M, Giorgetti A, Piccoli S, Cellini B, Voltattorni CB.

Hum Mol Genet. 2014 Oct 15;23(20):5429-40. doi: 10.1093/hmg/ddu266. Epub 2014 May 27.

PubMed [citation]
PMID:
24865461

The genetic and clinical characteristics of aromatic L-amino acid decarboxylase deficiency in mainland China.

Wen Y, Wang J, Zhang Q, Chen Y, Bao X.

J Hum Genet. 2020 Sep;65(9):759-769. doi: 10.1038/s10038-020-0770-6. Epub 2020 May 14.

PubMed [citation]
PMID:
32409695
PMCID:
PMC7387242

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005040793.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: LZTR1 c.1234C>T (p.Arg412Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 238628 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1234C>T was reported as a de-novo mutation in one Japanese child with symptoms of Noonan Syndrome in a poster presentation at a scientific meeting (Dateki et al, ESPE, 2018), indicating that the variant may be associated with Noonan Syndrome, however this occurrence has not (to the best of our knowledge) been subsequently published in a peer-reviewed journal. Therefore, this information does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no reports of c.1234C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating an impact on protein function have been published in the literature. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited 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: Jul 7, 2024