VCV000218424.45 - ClinVar

NM_000088.4(COL1A1):c.613C>G (p.Pro205Ala)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(22)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(10); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000088.4(COL1A1):c.613C>G (p.Pro205Ala)

Variation ID: 218424 Accession: VCV000218424.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.33 17: 50197978 (GRCh38) [ NCBI UCSC ] 17: 48275339 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 27, 2015	Oct 20, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000088.4:c.613C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000079.2:p.Pro205Ala	missense
NC_000017.11:g.50197978G>C
NC_000017.10:g.48275339G>C
NG_007400.1:g.8662C>G
LRG_1:g.8662C>G
LRG_1t1:c.613C>G	LRG_1p1:p.Pro205Ala

... more HGVS ... less HGVS

Protein change

P205A

Other names

Canonical SPDI

NC_000017.11:50197977:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00180 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00408

1000 Genomes Project 0.00180

1000 Genomes Project 30x 0.00187

Trans-Omics for Precision Medicine (TOPMed) 0.00299

The Genome Aggregation Database (gnomAD) 0.00331

The Genome Aggregation Database (gnomAD), exomes 0.00334

Exome Aggregation Consortium (ExAC) 0.00358

Links

ClinGen: CA249240 dbSNP: rs72667032 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COL1A1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2758	2962

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Feb 6, 2024	RCV000203035.15
not provided	Benign/Likely benign (8)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV000224220.36
Osteogenesis imperfecta	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 5, 2024	RCV000487429.22
Connective tissue disorder	Uncertain significance (1)	criteria provided, single submitter	Nov 1, 2016	RCV000659348.9
Infantile cortical hyperostosis	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001124961.12
Osteogenesis imperfecta type I	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001082142.16
Ehlers-Danlos syndrome, arthrochalasia type	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001124960.12
Ehlers-Danlos syndrome	Benign (1)	criteria provided, single submitter	Mar 11, 2022	RCV002277557.10
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Feb 1, 2019	RCV002354572.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Jun 19, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000257624.2 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015
Likely Benign (Sep 29, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280785.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Uncertain significance (Jun 01, 2016)	criteria provided, single submitter (GenePathDx_Criteria_classificationV2) Method: clinical testing	Osteogenesis imperfecta (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	GenePathDx, GenePath diagnostics Accession: SCV000574530.1 First in ClinVar: Apr 28, 2017 Last updated: Apr 28, 2017	Comment: 7 years old male child, a suspected case of osteogenesis imperfecta. History of recurrent long bone fractures after trivial falls. Sclera and dentition are apparently … (more) 7 years old male child, a suspected case of osteogenesis imperfecta. History of recurrent long bone fractures after trivial falls. Sclera and dentition are apparently normal. No family history of similar complaints. Next generation DNA sequencing peripheral blood sample has revealed the presence of the heterozygous variant c.613C>G in the COL1A1 gene. This variant is being called a â€œvariant of unknown significanceâ€ based on available evidence in the databases and in silico mutation prediction methods. Kindly correlate with the family history and clinical details. (less) Number of individuals with the variant: 1
Uncertain significance (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781159.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018
Benign (Jul 15, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332644.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (2) PubMed: 16786509‚ 20696291 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL1A1 Number of individuals with the variant: 1 Sex: mixed
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Osteogenesis imperfecta type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000627273.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Benign (Jul 02, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001143192.1 First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020	Publications: PubMed (7) PubMed: 8079666‚ 29946973‚ 15741671‚ 18028452‚ 16786509‚ 20696291‚ 19550437
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ehlers-Danlos syndrome, arthrochalasia type Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001283980.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Osteogenesis imperfecta Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001283981.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Infantile cortical hyperostosis Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001283982.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Dec 11, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001753692.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: This variant is associated with the following publications: (PMID: 30715774, 27884173, 8079666)
Benign (Jan 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002564745.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Benign (Mar 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ehlers-Danlos syndrome Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002565536.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Uncertain significance (Feb 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004242865.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Benign (Nov 29, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000883626.4 First in ClinVar: Jun 08, 2016 Last updated: Feb 20, 2024
Benign (Jan 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta (Autosomal dominant inheritance) Affected status: no Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812751.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Likely benign (Feb 01, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002661334.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197557.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Benign (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004140817.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: COL1A1: BS1, BS2 Number of individuals with the variant: 5
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807542.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930250.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973024.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
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Comment:

7 years old male child, a suspected case of osteogenesis imperfecta. History of recurrent long bone fractures after trivial falls. Sclera and dentition are apparently normal. No family history of similar complaints. Next generation DNA sequencing peripheral blood sample has revealed the presence of the heterozygous variant c.613C>G in the COL1A1 gene. This variant is being called a â€œvariant of unknown significanceâ€ based on available evidence in the databases and in silico mutation prediction methods. Kindly correlate with the family history and clinical details.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comparison of Bone Microarchitecture Between Adult Osteogenesis Imperfecta and Early-Onset Osteoporosis.	Rolvien T	Calcified tissue international	2018	PMID: 29946973
FKBP10 and Bruck syndrome: phenotypic heterogeneity or call for reclassification?	Shaheen R	American journal of human genetics	2010	PMID: 20696291
CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis.	Van Dijk FS	European journal of human genetics : EJHG	2009	PMID: 19550437
A novel arginine-to-cysteine substitution in the triple helical region of the alpha1(I) collagen chain in a family with an osteogenesis imperfecta/Ehlers-Danlos phenotype.	Lund A	Clinical genetics	2008	PMID: 18028452
Mutation analysis of COL1A1 and COL1A2 in patients diagnosed with osteogenesis imperfecta type I-IV.	Pollitt R	Human mutation	2006	PMID: 16786509
Molecular findings in Brazilian patients with osteogenesis imperfecta.	Reis FC	Journal of applied genetics	2005	PMID: 15741671
Mutation analysis of coding sequences for type I procollagen in individuals with low bone density.	Spotila LD	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	1994	PMID: 8079666
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL1A1	-	-	-	-

Text-mined citations for rs72667032 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000088.4(COL1A1):c.613C>G (p.Pro205Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72667032 ...