NM_000075.4(CDK4):c.218G>A (p.Arg73Gln) AND Hereditary melanoma

Clinical significance:Uncertain significance (Last evaluated: Apr 12, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001036844.2

Allele description [Variation Report for NM_000075.4(CDK4):c.218G>A (p.Arg73Gln)]

NM_000075.4(CDK4):c.218G>A (p.Arg73Gln)

Gene:
CDK4:cyclin dependent kinase 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q14.1
Genomic location:
Preferred name:
NM_000075.4(CDK4):c.218G>A (p.Arg73Gln)
HGVS:
  • NC_000012.12:g.57751500C>T
  • NG_007484.2:g.5882G>A
  • NM_000075.4:c.218G>AMANE SELECT
  • NP_000066.1:p.Arg73Gln
  • LRG_490:g.5882G>A
  • NC_000012.11:g.58145283C>T
  • NM_000075.3:c.218G>A
Protein change:
R73Q
Molecular consequence:
  • NM_000075.4:c.218G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary melanoma
Synonyms:
Hereditary cutaneous melanoma; Familial melanoma
Identifiers:
MONDO: MONDO:0018961; MedGen: C1512419

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001200228Invitaecriteria provided, single submitter
Uncertain significance
(Apr 12, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
PMID:
9536098
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001200228.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces arginine with glutamine at codon 73 of the CDK4 protein (p.Arg73Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 2 of the CDK4 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDK4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 7, 2021

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