NM_000093.5(COL5A1):c.5204G>A (p.Ser1735Asn) AND Ehlers-Danlos syndrome, classic type, 1

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 13, 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:: RCV002235045.14

Allele description [Variation Report for NM_000093.5(COL5A1):c.5204G>A (p.Ser1735Asn)]

NM_000093.5(COL5A1):c.5204G>A (p.Ser1735Asn)

Genes:

COL5A1:collagen type V alpha 1 chain [Gene - OMIM - HGNC]
LOC101448202:uncharacterized LOC101448202 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.3

Genomic location:

Preferred name:

NM_000093.5(COL5A1):c.5204G>A (p.Ser1735Asn)

HGVS:

NC_000009.12:g.134835038G>A
NG_008030.1:g.198233G>A
NM_000093.5:c.5204G>AMANE SELECT
NM_001278074.1:c.5204G>A
NP_000084.3:p.Ser1735Asn
NP_000084.3:p.Ser1735Asn
NP_001265003.1:p.Ser1735Asn
LRG_737t1:c.5204G>A
LRG_737t2:c.5204G>A
LRG_737:g.198233G>A
LRG_737p1:p.Ser1735Asn
LRG_737p2:p.Ser1735Asn
NC_000009.11:g.137726884G>A
NM_000093.3:c.5204G>A
NM_000093.4:c.5204G>A

Protein change:

S1735N

Links:

dbSNP: rs1588615451

NCBI 1000 Genomes Browser:

rs1588615451

Molecular consequence:

NM_000093.5:c.5204G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278074.1:c.5204G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000955332	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 5, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004036005	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Uncertain significance (Apr 13, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000955332

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 5, 2018)

germline

clinical testing

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

SCV004036005

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Uncertain significance
(Apr 13, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000955332.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 C0"). This variant has been observed to be de novo in an individual with clinical features of Ehlers-Danlos syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1735 of the COL5A1 protein (p.Ser1735Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV004036005.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The COL5A1 c.5204G>A (p.Ser1735Asn) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.5204G>A (p.Ser1735Asn) variant is classified as a variant of uncertain significance for classic Ehlers-Danlos syndrome.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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