NM_001853.4(COL9A3):c.1378G>A (p.Gly460Ser) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Dec 25, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000658918.26

Allele description

NM_001853.4(COL9A3):c.1378G>A (p.Gly460Ser)

Genes:

LOC126863084:MED14-independent group 3 enhancer GRCh37_chr20:61467141-61468340 [Gene]
COL9A3:collagen type IX alpha 3 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.33

Genomic location:

Preferred name:

NM_001853.4(COL9A3):c.1378G>A (p.Gly460Ser)

HGVS:

NC_000020.11:g.62835930G>A
NG_016353.1:g.23869G>A
NM_001853.4:c.1378G>AMANE SELECT
NP_001844.3:p.Gly460Ser
LRG_1253t1:c.1378G>A
LRG_1253:g.23869G>A
LRG_1253p1:p.Gly460Ser
NC_000020.10:g.61467282G>A
NM_001853.3:c.1378G>A

Protein change:

G460S

Links:

dbSNP: rs148610956

NCBI 1000 Genomes Browser:

rs148610956

Molecular consequence:

NM_001853.4:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000780719	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Feb 1, 2018)	germline	clinical testing	Citation Link,
SCV000863143	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Aug 22, 2018)	germline	clinical testing	Citation Link,
SCV001765890	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 31, 2023)	germline	clinical testing	Citation Link,
SCV002288028	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	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 CeGaT Center for Human Genetics Tuebingen, SCV000780719.23

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

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

From Eurofins Ntd Llc (ga), SCV000863143.1

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV001765890.2

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

Description

Identified in a patient with hearing loss and myopathy, who also had a homozogyous STRC gene deletion (Morgan et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35052694)

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

From Invitae, SCV002288028.3

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 460 of the COL9A3 protein (p.Gly460Ser). This variant is present in population databases (rs148610956, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with COL9A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 546902). 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 COL9A3 protein function with a positive predictive value of 95%. 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.

#	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

Last Updated: Apr 15, 2024

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