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NM_000093.5(COL5A1):c.1561A>G (p.Met521Val) AND Ehlers-Danlos syndrome, classic type, 1

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jul 17, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV002228840.13

Allele description [Variation Report for NM_000093.5(COL5A1):c.1561A>G (p.Met521Val)]

NM_000093.5(COL5A1):c.1561A>G (p.Met521Val)

Gene:
COL5A1:collagen type V alpha 1 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q34.3
Genomic location:
Preferred name:
NM_000093.5(COL5A1):c.1561A>G (p.Met521Val)
Other names:
p.M521V:ATG>GTG
HGVS:
  • NC_000009.12:g.134750608A>G
  • NG_008030.1:g.113803A>G
  • NM_000093.5:c.1561A>GMANE SELECT
  • NM_001278074.1:c.1561A>G
  • NP_000084.3:p.Met521Val
  • NP_000084.3:p.Met521Val
  • NP_001265003.1:p.Met521Val
  • LRG_737t1:c.1561A>G
  • LRG_737t2:c.1561A>G
  • LRG_737:g.113803A>G
  • LRG_737p1:p.Met521Val
  • LRG_737p2:p.Met521Val
  • NC_000009.11:g.137642454A>G
  • NM_000093.3:c.1561A>G
  • NM_000093.4:c.1561A>G
Protein change:
M521V
Links:
dbSNP: rs535161301
NCBI 1000 Genomes Browser:
rs535161301
Molecular consequence:
  • NM_000093.5:c.1561A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278074.1:c.1561A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Ehlers-Danlos syndrome, classic type, 1 (EDSCL1)
Synonyms:
EHLERS-DANLOS SYNDROME, GRAVIS TYPE; EHLERS-DANLOS SYNDROME, SEVERE CLASSIC TYPE; Ehlers-Danlos syndrome, type 1; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0019567; MedGen: C0268335; OMIM: 130000

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000549009Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Benign
(Jun 28, 2023) 		germlineclinical testing

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

SCV005086558Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jul 17, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot 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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Identification of the novel COL5A1 c.3369_3431dup, p.(Glu1124_Gly1144dup) variant in a patient with incomplete classical Ehlers-Danlos syndrome: The importance of phenotype-guided genetic testing.

Ritelli M, Cinquina V, Venturini M, Colombi M.

Mol Genet Genomic Med. 2020 Oct;8(10):e1422. doi: 10.1002/mgg3.1422. Epub 2020 Jul 28.

PubMed [citation]
PMID:
32720758
PMCID:
PMC7549590
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549009.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086558.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with classic type Ehlers-Danlos syndrome 1 (MIM#130000) whereas the mechanism of disease for multifocal fibromuscular dysplasia (MIM#619329) is unknown. Dominant negative is a suggested mechanism of disease (PMID: 32720758). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2 & v3: 5 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (Clinvar). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Nov 3, 2024