VCV000213047.45 - ClinVar

NM_000093.5(COL5A1):c.3023C>T (p.Thr1008Met)

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.

(9)

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(6); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000093.5(COL5A1):c.3023C>T (p.Thr1008Met)

Variation ID: 213047 Accession: VCV000213047.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 134802904 (GRCh38) [ NCBI UCSC ] 9: 137694750 (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 6, 2016	Nov 17, 2024	Jan 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000093.5:c.3023C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000084.3:p.Thr1008Met	missense
NM_001278074.1:c.3023C>T	NP_001265003.1:p.Thr1008Met	missense
NC_000009.12:g.134802904C>T
NC_000009.11:g.137694750C>T
NG_008030.1:g.166099C>T
LRG_737:g.166099C>T
LRG_737t1:c.3023C>T	LRG_737p1:p.Thr1008Met
LRG_737t2:c.3023C>T	LRG_737p2:p.Thr1008Met

... more HGVS ... less HGVS

Protein change

T1008M

Other names

p.T1008M:ACG>ATG

Canonical SPDI

NC_000009.12:134802903:C:T

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

Links

ClinGen: CA323683 dbSNP: rs199735010 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.
COL5A1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2689	3496

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 provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Nov 9, 2022	RCV000199147.32
Ehlers-Danlos syndrome type 7A	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000279787.7
Ehlers-Danlos syndrome, classic type	Likely benign (2)	criteria provided, single submitter	Jan 13, 2018	RCV000509160.11
Ehlers-Danlos syndrome, classic type, 1	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 20, 2024	RCV002229075.10
Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (1)	criteria provided, single submitter	Sep 7, 2023	RCV002433874.6

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.
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Ehlers-Danlos Syndrome, Type VIIA Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000478552.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Nov 09, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000249906.14 First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022	Comment: Identified in an infant with seizures, apnea, periodic fever, hypotonia, gastroesophageal reflux, atrial septal aneurysm, patent foramen ovale, fragile blood vessels and easy bruising in … (more) Identified in an infant with seizures, apnea, periodic fever, hypotonia, gastroesophageal reflux, atrial septal aneurysm, patent foramen ovale, fragile blood vessels and easy bruising in published literature (Dobrucka-Glowacka et al., 2018); however, no segregation studies were reported; Has been reported as a likely benign variant in a two generation family with soft, velvety skin, joint dislocations, and arthralgia (Junkiert-Czarnecka et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (Symoens et al., 2012; HGMD).; This variant is associated with the following publications: (PMID: 35723357, 22696272) (less)
Likely benign (Jan 20, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ehlers-Danlos syndrome, classic type, 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000832763.5 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ehlers-Danlos syndrome, classic type, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001331398.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Uncertain significance (Sep 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714939.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 2
Uncertain significance (Sep 07, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002754300.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 35723357 Comment: The p.T1008M variant (also known as c.3023C>T), located in coding exon 39 of the COL5A1 gene, results from a C to T substitution at nucleotide … (more) The p.T1008M variant (also known as c.3023C>T), located in coding exon 39 of the COL5A1 gene, results from a C to T substitution at nucleotide position 3023. The threonine at codon 1008 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in an Ehlers-Danlos syndrome cohort (Junkiert-Czarnecka A et al. Curr Issues Mol Biol, 2022 Mar;44:1472-1478). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Dec 01, 2021)	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: SCV002063275.20 First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Jun 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ehlers-Danlos syndrome, classic type, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397237.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Comment: This sequence variant is a single nucleotide substitution (C>T) at coding position 3023 of the COL5A1 gene that results in a threonine to methionine amino … (more) This sequence variant is a single nucleotide substitution (C>T) at coding position 3023 of the COL5A1 gene that results in a threonine to methionine amino acid change at residue 1008 of the COL5A1 protein. This is a previously reported variant (ClinVar) that has not been observed in the literature in individuals with COL5A1-related illness, to our knowledge. This variant is present in control population datasets (gnomAD database 21 of 277202 alleles or 0.0075%). Multiple bioinformatic tools predict that this variant would be damaging, and the Thr1008 residue is highly conserved across the mammalian species examined. Functiol studies testing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: BP1 (less)
not provided (-)	no classification provided Method: phenotyping only	Ehlers-Danlos syndrome, classic type, 1 Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607028.1 First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) … (more) Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) , Obesity (present) , Overgrowth (present) , Abnormality of the parathyroid physiology (present) , Hyperthyroidism (present) , Goiter (present) , Adrenal hyperplasia (present) , Hypogonadism (present) , Precocious puberty (present) , Diabetes insipidus (present) , Delayed puberty (present) , Type I diabetes mellitus (present) , Type II diabetes mellitus (present) , Ptosis (present) , Abnormality of the retina (present) , Abnormality of the optic nerve (present) , Hypermetropia (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of the lens (present) , Abnormality of the iris (present) , Abnormality of globe size (present) , Abnormality of eye movement (present) , Seizures (present) , Parkinsonism (present) , Abnormality of movement (present) , Memory impairment (present) , Generalized hypotonia (present) , Hypertonia (present) , Encephalopathy (present) , EEG abnormality (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Cerebral palsy (present) , Morphological abnormality of the central nervous system (present) , Short attention span (present) , Psychosis (present) , Obsessive-compulsive behavior (present) , Hallucinations (present) , Delusions (present) , Depression (present) , Anxiety (present) , Abnormal aggressive, impulsive or violent behavior (present) , Stereotypy (present) , Schizophrenia (present) , Bipolar affective disorder (present) , Autistic behavior (present) , Cutis laxa (present) , Hyperextensible skin (present) , Epidermal thickening (present) , Generalized abnormality of skin (present) , Hyperhidrosis (present) , Hypohidrosis (present) , Hypopigmentation of the skin (present) , Hyperpigmentation of the skin (present) , Multiple cafe-au-lait spots (present) , Atrophic scars (present) , Skeletal dysplasia (present) , Pectus excavatum (present) , Pectus carinatum (present) , Hip dysplasia (present) , Abnormality of digit (present) , Increased susceptibility to fractures (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of limb bone morphology (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , EMG abnormality (present) , Abnormality of muscle morphology (present) , Abnormality of muscle physiology (present) , Abnormality of facial musculature (present) , Abnormality of the anus (present) , Abnormality of the large intestine (present) , Abnormality of the intestine (present) , Gastrointestinal dysmotility (present) , Abnormality of the liver (present) , Abnormality of the pancreas (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Feeding difficulties (present) , Rheumatoid arthritis (present) , Recurrent infections (present) , Abnormal inflammatory response (present) , Immunodeficiency (present) , Autoimmunity (present) (less) Age: 10-19 years Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2017-01-24 Testing laboratory interpretation: Uncertain significance

Comment:

Identified in an infant with seizures, apnea, periodic fever, hypotonia, gastroesophageal reflux, atrial septal aneurysm, patent foramen ovale, fragile blood vessels and easy bruising in published literature (Dobrucka-Glowacka et al., 2018); however, no segregation studies were reported; Has been reported as a likely benign variant in a two generation family with soft, velvety skin, joint dislocations, and arthralgia (Junkiert-Czarnecka et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (Symoens et al., 2012; HGMD).; This variant is associated with the following publications: (PMID: 35723357, 22696272)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

The p.T1008M variant (also known as c.3023C>T), located in coding exon 39 of the COL5A1 gene, results from a C to T substitution at nucleotide position 3023. The threonine at codon 1008 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in an Ehlers-Danlos syndrome cohort (Junkiert-Czarnecka A et al. Curr Issues Mol Biol, 2022 Mar;44:1472-1478). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence variant is a single nucleotide substitution (C>T) at coding position 3023 of the COL5A1 gene that results in a threonine to methionine amino acid change at residue 1008 of the COL5A1 protein. This is a previously reported variant (ClinVar) that has not been observed in the literature in individuals with COL5A1-related illness, to our knowledge. This variant is present in control population datasets (gnomAD database 21 of 277202 alleles or 0.0075%). Multiple bioinformatic tools predict that this variant would be damaging, and the Thr1008 residue is highly conserved across the mammalian species examined. Functiol studies testing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: BP1

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome.	Junkiert-Czarnecka A	Current issues in molecular biology	2022	PMID: 35723357

Text-mined citations for rs199735010 ...

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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000093.5(COL5A1):c.3023C>T (p.Thr1008Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199735010 ...