NM_001851.6(COL9A1):c.1634G>A (p.Arg545His) AND not provided

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

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Nov 28, 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:: RCV000344967.15

Allele description

NM_001851.6(COL9A1):c.1634G>A (p.Arg545His)

Gene:

COL9A1:collagen type IX alpha 1 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q13

Genomic location:

Preferred name:

NM_001851.6(COL9A1):c.1634G>A (p.Arg545His)

HGVS:

NC_000006.12:g.70254994C>T
NG_011654.1:g.53090G>A
NM_001377289.1:c.905G>A
NM_001377290.1:c.905G>A
NM_001851.6:c.1634G>AMANE SELECT
NM_078485.4:c.905G>A
NP_001364218.1:p.Arg302His
NP_001364219.1:p.Arg302His
NP_001842.3:p.Arg545His
NP_511040.2:p.Arg302His
NC_000006.11:g.70964697C>T
NM_001851.4:c.1634G>A
NR_165185.1:n.1155G>A

Protein change:

R302H

Links:

dbSNP: rs145698301

NCBI 1000 Genomes Browser:

rs145698301

Molecular consequence:

NM_001377289.1:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001377290.1:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001851.6:c.1634G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_078485.4:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_165185.1:n.1155G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000334750	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Sep 16, 2015)	germline	clinical testing	Citation Link,
SCV001420252	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Nov 28, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001553758	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV002007366	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 14, 2021)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	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
not provided	unknown	yes	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 Eurofins Ntd Llc (ga), SCV000334750.4

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001420252.5

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

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553758.1

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

Description

The COL9A1 p.R545H variant was not identified in the literature nor was it identified in LOVD 3.0, however it was identified in dbSNP (ID: rs145698301) and in ClinVar (classified as uncertain significance by EGL Genetic Diagnostics and Fulgent Genetics for Stickler syndrome type 4 and Multiple epiphyseal dysplasia 6). The variant was identified in control databases in 38 of 282812 chromosomes at a frequency of 0.0001344 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 20 of 24964 chromosomes (freq: 0.000801), European (non-Finnish) in 14 of 129152 chromosomes (freq: 0.000108), South Asian in 2 of 30610 chromosomes (freq: 0.000065) and Latino in 2 of 35426 chromosomes (freq: 0.000056), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Arg545 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

From GeneDx, SCV002007366.2

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

Description

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 282983; Landrum et al., 2016)

#	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

Last Updated: Sep 29, 2024

ClinVar

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