NM_000089.4(COL1A2):c.1658G>A (p.Gly553Asp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 13, 2019
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:: RCV000255044.10

Allele description [Variation Report for NM_000089.4(COL1A2):c.1658G>A (p.Gly553Asp)]

NM_000089.4(COL1A2):c.1658G>A (p.Gly553Asp)

Gene:

COL1A2:collagen type I alpha 2 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q21.3

Genomic location:

Preferred name:

NM_000089.4(COL1A2):c.1658G>A (p.Gly553Asp)

HGVS:

NC_000007.14:g.94413940G>A
NG_007405.1:g.24380G>A
NM_000089.4:c.1658G>AMANE SELECT
NP_000080.2:p.Gly553Asp
NP_000080.2:p.Gly553Asp
LRG_2t1:c.1658G>A
LRG_2:g.24380G>A
LRG_2p1:p.Gly553Asp
NC_000007.13:g.94043252G>A
NM_000089.3:c.1658G>A

Protein change:

G553D

Links:

dbSNP: rs72658137

NCBI 1000 Genomes Browser:

rs72658137

Molecular consequence:

NM_000089.4:c.1658G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322229	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 13, 2019)	germline	clinical testing	Citation Link,
SCV000885222	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Mar 1, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322229

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 13, 2019)

germline

clinical testing

Citation Link,

SCV000885222

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Mar 1, 2018)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000322229.6

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

Description

Located in the triple-helical region; replaces the Gly in the canonical Gly-X-Y repeat; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25525159, 17078022)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885222.1

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

Description

The p.Gly553Asp variant (rs72658137) has been reported in one patient with osteogenesis imperfecta type II (Marini 2007). This variant is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD). The p.Gly553Asp variant affects a highly conserved glycine located in the triple helical domain composed of uninterrupted repeats of the Gly-X-Y tripeptide, and all computation prediction algorithms indicate a deleterious effect on protein structure and function (SIFT: damaging, PolyPhen-2:probably damaging). Variants that disrupt this tripeptide sequence are reported to result in impaired collagen function (Ben Amor 2011). Based on the above information, this variant is considered pathogenic.

#	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: Mar 4, 2023

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