NM_001844.5(COL2A1):c.4064G>A (p.Gly1355Asp) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Jan 6, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000079727.8

Allele description [Variation Report for NM_001844.5(COL2A1):c.4064G>A (p.Gly1355Asp)]

NM_001844.5(COL2A1):c.4064G>A (p.Gly1355Asp)

Gene:
COL2A1:collagen type II alpha 1 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q13.11
Genomic location:
Preferred name:
NM_001844.5(COL2A1):c.4064G>A (p.Gly1355Asp)
HGVS:
  • NC_000012.12:g.47974685C>T
  • NG_008072.1:g.34818G>A
  • NM_001844.5:c.4064G>AMANE SELECT
  • NM_033150.3:c.3857G>A
  • NP_001835.3:p.Gly1355Asp
  • NP_001835.3:p.Gly1355Asp
  • NP_149162.2:p.Gly1286Asp
  • NC_000012.11:g.48368468C>T
  • NM_001844.4:c.4064G>A
Protein change:
G1286D
Links:
dbSNP: rs201646745
NCBI 1000 Genomes Browser:
rs201646745
Molecular consequence:
  • NM_001844.5:c.4064G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033150.3:c.3857G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000111610EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Aug 21, 2017)
germlineclinical testing

Citation Link,

SCV001208530Invitaecriteria provided, single submitter
Uncertain significance
(Sep 24, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001778633GeneDxcriteria provided, single submitter
Uncertain significance
(Jan 6, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown2not providednot providednot providednot providedclinical testing

Citations

PubMed

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 EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000111610.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

From Invitae, SCV001208530.2

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

Description

This sequence change replaces glycine with aspartic acid at codon 1355 of the COL2A1 protein (p.Gly1355Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs201646745, ExAC 0.01%). This variant has not been reported in the literature in individuals with COL2A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 93790). 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: Not Available; Align-GVGD: Class C). 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. 5

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

From GeneDx, SCV001778633.1

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

Description

Has been reported with a COL4A1 de novo pathogenic variant in an individual with small vessel cerebral disease, cardiomegaly and right ventricular hypertrophy (England et al., 2020); however the patient's father carried the COL2A1 variant and was phenotypically normal.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 33057775)

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

Last Updated: Sep 12, 2021

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