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NM_001378615.1(CC2D2A):c.4550C>T (p.Thr1517Ile) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 10, 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:
RCV000821855.5

Allele description [Variation Report for NM_001378615.1(CC2D2A):c.4550C>T (p.Thr1517Ile)]

NM_001378615.1(CC2D2A):c.4550C>T (p.Thr1517Ile)

Gene:
CC2D2A:coiled-coil and C2 domain containing 2A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4p15.32
Genomic location:
Preferred name:
NM_001378615.1(CC2D2A):c.4550C>T (p.Thr1517Ile)
HGVS:
  • NC_000004.12:g.15599582C>T
  • NG_013035.1:g.134717C>T
  • NM_001080522.2:c.4550C>T
  • NM_001378615.1:c.4550C>TMANE SELECT
  • NM_001378617.1:c.4403C>T
  • NP_001073991.2:p.Thr1517Ile
  • NP_001365544.1:p.Thr1517Ile
  • NP_001365546.1:p.Thr1468Ile
  • LRG_697t1:c.4550C>T
  • LRG_697:g.134717C>T
  • LRG_697p1:p.Thr1517Ile
  • NC_000004.11:g.15601205C>T
Protein change:
T1468I
Links:
dbSNP: rs780673487
NCBI 1000 Genomes Browser:
rs780673487
Molecular consequence:
  • NM_001080522.2:c.4550C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378615.1:c.4550C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378617.1:c.4403C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial aplasia of the vermis
Synonyms:
CEREBELLOPARENCHYMAL DISORDER IV; Joubert syndrome; Cerebelloparenchymal disorder 4; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300
Name:
Meckel-Gruber syndrome
Synonyms:
DYSENCEPHALIA SPLANCHNOCYSTICA; Gruber syndrome; Dysencephalia splachnocystica
Identifiers:
MONDO: MONDO:0018921; MedGen: C0265215; OMIM: PS249000

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000962627Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Mar 10, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

First-trimester diagnosis of Meckel-Gruber syndrome by fetal ultrasound with molecular identification of CC2D2A mutations by next-generation sequencing.

Jones D, Fiozzo F, Waters B, McKnight D, Brown S.

Ultrasound Obstet Gynecol. 2014 Dec;44(6):719-21. doi: 10.1002/uog.13381. Epub 2014 Oct 27.

PubMed [citation]
PMID:
24706459

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000962627.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr1517 amino acid residue in CC2D2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24706459). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CC2D2A protein function. ClinVar contains an entry for this variant (Variation ID: 663886). This missense change has been observed in individual(s) with clinical features of Joubert syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1517 of the CC2D2A protein (p.Thr1517Ile).

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

Last Updated: Mar 5, 2024