NM_000088.4(COL1A1):c.4328C>T (p.Ala1443Val) AND Osteogenesis imperfecta type I

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 17, 2024
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:: RCV000496049.13

Allele description [Variation Report for NM_000088.4(COL1A1):c.4328C>T (p.Ala1443Val)]

NM_000088.4(COL1A1):c.4328C>T (p.Ala1443Val)

Gene:

COL1A1:collagen type I alpha 1 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.33

Genomic location:

Preferred name:

NM_000088.4(COL1A1):c.4328C>T (p.Ala1443Val)

HGVS:

NC_000017.11:g.50185569G>A
NG_007400.1:g.21071C>T
NM_000088.4:c.4328C>TMANE SELECT
NP_000079.2:p.Ala1443Val
NP_000079.2:p.Ala1443Val
LRG_1t1:c.4328C>T
LRG_1:g.21071C>T
LRG_1p1:p.Ala1443Val
NC_000017.10:g.48262930G>A
NM_000088.3:c.4328C>T

Protein change:

A1443V

Links:

dbSNP: rs1131692326

NCBI 1000 Genomes Browser:

rs1131692326

Molecular consequence:

NM_000088.4:c.4328C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Osteogenesis imperfecta type I (OI1)
Synonyms:: OI, TYPE I; OSTEOGENESIS IMPERFECTA TARDA; OSTEOGENESIS IMPERFECTA WITH BLUE SCLERAE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008146; MedGen: C0023931; Orphanet: 666; OMIM: 166200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000584182	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	criteria provided, single submitter (ACGS Guidelines, 2020)	Likely pathogenic (May 17, 2024)	unknown	clinical testing	Citation Link,
SCV000962312	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30614853, 33939306, 28492532
SCV002579637	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000584182

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

criteria provided, single submitter

(ACGS Guidelines, 2020)

Likely pathogenic
(May 17, 2024)

unknown

clinical testing

Citation Link,

SCV000962312

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002579637

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 15, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	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
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype relationship in a large cohort of osteogenesis imperfecta patients with COL1A1 mutations revealed by a new scoring system.

Li LJ, Lyu F, Song YW, Wang O, Jiang Y, Xia WB, Xing XP, Li M.

Chin Med J (Engl). 2019 Jan 20;132(2):145-153. doi: 10.1097/CM9.0000000000000013.

PubMed [citation]

PMID:: 30614853
PMCID:: PMC6365277

Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands.

Higuchi Y, Hasegawa K, Futagawa N, Yamashita M, Tanaka H, Tsukahara H.

Mol Genet Genomic Med. 2021 Jun;9(6):e1675. doi: 10.1002/mgg3.1675. Epub 2021 May 3.

PubMed [citation]

PMID:: 33939306
PMCID:: PMC8222851

See all PubMed Citations (4)

Details of each submission

From Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues, SCV000584182.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000962312.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1443 of the COL1A1 protein (p.Ala1443Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of osteogenesis imperfecta and/or osteogenesis imperfecta (PMID: 30614853, 33939306; Invitae). ClinVar contains an entry for this variant (Variation ID: 431035). 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 COL1A1 protein function. For these reasons, this variant has been classified as 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

From MGZ Medical Genetics Center, SCV002579637.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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