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NM_001846.4(COL4A2):c.2453G>T (p.Gly818Val) AND Porencephaly 2

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 17, 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:
RCV004595322.1

Allele description [Variation Report for NM_001846.4(COL4A2):c.2453G>T (p.Gly818Val)]

NM_001846.4(COL4A2):c.2453G>T (p.Gly818Val)

Gene:
COL4A2:collagen type IV alpha 2 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q34
Genomic location:
Preferred name:
NM_001846.4(COL4A2):c.2453G>T (p.Gly818Val)
HGVS:
  • NC_000013.11:g.110478030G>T
  • NG_032137.1:g.175747G>T
  • NG_032137.2:g.175748G>T
  • NM_001846.4:c.2453G>TMANE SELECT
  • NP_001837.2:p.Gly818Val
  • NC_000013.10:g.111130377G>T
  • NM_001846.3:c.2453G>T
Protein change:
G818V
Molecular consequence:
  • NM_001846.4:c.2453G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Porencephaly 2 (BSVD2)
Synonyms:
BRAIN SMALL VESSEL DISEASE 2
Identifiers:
MONDO: MONDO:0013773; MedGen: C3280970; Orphanet: 2940; Orphanet: 99810; OMIM: 614483

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005086493Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jul 17, 2023) 		germlineclinical testing

PubMed (6)
[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

De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly.

Yoneda Y, Haginoya K, Arai H, Yamaoka S, Tsurusaki Y, Doi H, Miyake N, Yokochi K, Osaka H, Kato M, Matsumoto N, Saitsu H.

Am J Hum Genet. 2012 Jan 13;90(1):86-90. doi: 10.1016/j.ajhg.2011.11.016. Epub 2011 Dec 29.

PubMed [citation]
PMID:
22209246
PMCID:
PMC3257897

COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.

Jeanne M, Labelle-Dumais C, Jorgensen J, Kauffman WB, Mancini GM, Favor J, Valant V, Greenberg SM, Rosand J, Gould DB.

Am J Hum Genet. 2012 Jan 13;90(1):91-101. doi: 10.1016/j.ajhg.2011.11.022. Epub 2011 Dec 29.

PubMed [citation]
PMID:
22209247
PMCID:
PMC3257894
See all PubMed Citations (6)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086493.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. It appears that the mechanism resembles that of the COL4A1 gene, including loss-of-function and dominant negative, the latter resulting from Gly substitutions on the G-X-Y motif (PMIDs: 22209246, 22209247, 24001601). (I) 0107 - This gene is associated with autosomal dominant disease. However, there is emerging evidence of biallelic inheritance leading to intellectual disability, epilepsy, and spastic cerebral palsy (PMID: 33912663). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 33912663). (I) 0115 - Variants in this gene are known to have variable expressivity. The severity of phenotypes varies greatly (PMID: 27794444). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional Gly-X-Y motif within the collagen repeat domain, and affects a glycine residue (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Aug 4, 2024