This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 430 of the COLQ protein (p.Tyr430Ser). This variant is present in population databases (rs121908923, gnomAD 0.02%). This missense change has been observed in individuals with congenital myasthenic syndrome (PMID: 9758617, 29054425). It has also been observed to segregate with disease in related individuals. This variant is also known as Y431S. ClinVar contains an entry for this variant (Variation ID: 6654). 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 not expected to disrupt COLQ protein function. Experimental studies have shown that this missense change affects COLQ function (PMID: 15159418). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005677.4(COLQ):c.1289A>C (p.Tyr430Ser)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005677.4(COLQ):c.1289A>C (p.Tyr430Ser)
Variation ID: 6654 Accession: VCV000006654.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15453838 (GRCh38) [ NCBI UCSC ] 3: 15495345 (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 May 1, 2015 Oct 8, 2024 Mar 18, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005677.4:c.1289A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005668.2:p.Tyr430Ser missense NM_005677.3:c.1289A>C NM_080538.2:c.1259A>C NP_536799.1:p.Tyr420Ser missense NM_080539.4:c.1187A>C NP_536800.2:p.Tyr396Ser missense NC_000003.12:g.15453838T>G NC_000003.11:g.15495345T>G NG_009032.2:g.72914A>C Q9Y215:p.Tyr430Ser - Protein change
- Y430S, Y396S, Y420S
- Other names
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Y431S
- Canonical SPDI
- NC_000003.12:15453837:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
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Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| COLQ | - | - |
GRCh38 GRCh37 |
578 | 604 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 10, 2024 | RCV000007033.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2022 | RCV001813737.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 18, 2024 | RCV004526590.2 | |
|
COLQ-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 26, 2024 | RCV004757099.1 |
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. |
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|---|---|---|---|---|---|
|
Pathogenic
(Apr 30, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome 5
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019704.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Feb 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001579178.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 430 of the COLQ protein (p.Tyr430Ser). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 430 of the COLQ protein (p.Tyr430Ser). This variant is present in population databases (rs121908923, gnomAD 0.02%). This missense change has been observed in individuals with congenital myasthenic syndrome (PMID: 9758617, 29054425). It has also been observed to segregate with disease in related individuals. This variant is also known as Y431S. ClinVar contains an entry for this variant (Variation ID: 6654). 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 not expected to disrupt COLQ protein function. Experimental studies have shown that this missense change affects COLQ function (PMID: 15159418). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Mar 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039838.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: COLQ c.1289A>C (p.Tyr430Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: COLQ c.1289A>C (p.Tyr430Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 245298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COLQ causing Congenital Myasthenic Syndrome (4.1e-05 vs 0.0014), allowing no conclusion about variant significance. c.1289A>C has been reported in the literature in multiple homozygous individuals affected with Congenital Myasthenic Syndrome (e.g. Abicht_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22678886). ClinVar contains an entry for this variant (Variation ID: 6654). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Myasthenic syndrome, slow-channel congenital
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061294.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.1289A>C;p.(Tyr430Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 6654; PMID: 29054425) - PS4.The … (more)
The c.1289A>C;p.(Tyr430Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 6654; PMID: 29054425) - PS4.The variant is present at low allele frequencies population databases (rs121908923– gnomAD 0.0004608%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Tyr430Ser) was detected in trans with a pathogenic variant (PMID: 29054425) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Uruguay
|
|
|
Pathogenic
(Mar 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myasthenic syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004214440.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Oct 01, 1998)
|
no assertion criteria provided
Method: literature only
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MYASTHENIC SYNDROME, CONGENITAL, 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027229.2
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2015 |
Comment on evidence:
In 6 affected sibs from a consanguineous Spanish family with congenital myasthenic syndrome-5 (CMS5; 603034), Donger et al. (1998) identified a homozygous tyr431-to-ser (Y431S) substitution … (more)
In 6 affected sibs from a consanguineous Spanish family with congenital myasthenic syndrome-5 (CMS5; 603034), Donger et al. (1998) identified a homozygous tyr431-to-ser (Y431S) substitution in the conserved C-terminal domain of COLQ. The mutation was predicted to disturb the attachment of collagen-tailed acetylcholinesterase to the neuromuscular junction (NMJ). Donger et al. (1998) referred to the disorder in these patients as CMS Ic (for congenital myasthenic syndrome type Ic). The authors noted that most previously described CMS Ic patients had a marked decrease in total muscle acetylcholinesterase with essentially no collagen-tailed forms. These forms were present in affected members of the Spanish family, but the defect interfered with attachment to the NMJ. (less)
|
|
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Pathogenic
(Sep 26, 2024)
|
no assertion criteria provided
Method: clinical testing
|
COLQ-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005347547.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The COLQ c.1289A>C variant is predicted to result in the amino acid substitution p.Tyr430Ser. This variant has been reported in the homozygous state in several … (more)
The COLQ c.1289A>C variant is predicted to result in the amino acid substitution p.Tyr430Ser. This variant has been reported in the homozygous state in several siblings in a large family to be causative for congenital myasthenic syndrome (Donger et al. 1998. PubMed ID: 9758617). This variant has also been reported in the compound heterozygous state in several additional individuals with congenital myasthenic syndrome (Servais et al. 2012. PubMed ID: 23108489; Natera-de Benito et al. 2017. PubMed ID: 29054425). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
Variant summary: COLQ c.1289A>C (p.Tyr430Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 245298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COLQ causing Congenital Myasthenic Syndrome (4.1e-05 vs 0.0014), allowing no conclusion about variant significance. c.1289A>C has been reported in the literature in multiple homozygous individuals affected with Congenital Myasthenic Syndrome (e.g. Abicht_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22678886). ClinVar contains an entry for this variant (Variation ID: 6654). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.1289A>C;p.(Tyr430Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 6654; PMID: 29054425) - PS4.The variant is present at low allele frequencies population databases (rs121908923– gnomAD 0.0004608%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Tyr430Ser) was detected in trans with a pathogenic variant (PMID: 29054425) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The COLQ c.1289A>C variant is predicted to result in the amino acid substitution p.Tyr430Ser. This variant has been reported in the homozygous state in several siblings in a large family to be causative for congenital myasthenic syndrome (Donger et al. 1998. PubMed ID: 9758617). This variant has also been reported in the compound heterozygous state in several additional individuals with congenital myasthenic syndrome (Servais et al. 2012. PubMed ID: 23108489; Natera-de Benito et al. 2017. PubMed ID: 29054425). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.
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 sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 430 of the COLQ protein (p.Tyr430Ser). This variant is present in population databases (rs121908923, gnomAD 0.02%). This missense change has been observed in individuals with congenital myasthenic syndrome (PMID: 9758617, 29054425). It has also been observed to segregate with disease in related individuals. This variant is also known as Y431S. ClinVar contains an entry for this variant (Variation ID: 6654). 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 not expected to disrupt COLQ protein function. Experimental studies have shown that this missense change affects COLQ function (PMID: 15159418). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: COLQ c.1289A>C (p.Tyr430Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 245298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COLQ causing Congenital Myasthenic Syndrome (4.1e-05 vs 0.0014), allowing no conclusion about variant significance. c.1289A>C has been reported in the literature in multiple homozygous individuals affected with Congenital Myasthenic Syndrome (e.g. Abicht_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22678886). ClinVar contains an entry for this variant (Variation ID: 6654). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.1289A>C;p.(Tyr430Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 6654; PMID: 29054425) - PS4.The variant is present at low allele frequencies population databases (rs121908923– gnomAD 0.0004608%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Tyr430Ser) was detected in trans with a pathogenic variant (PMID: 29054425) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The COLQ c.1289A>C variant is predicted to result in the amino acid substitution p.Tyr430Ser. This variant has been reported in the homozygous state in several siblings in a large family to be causative for congenital myasthenic syndrome (Donger et al. 1998. PubMed ID: 9758617). This variant has also been reported in the compound heterozygous state in several additional individuals with congenital myasthenic syndrome (Servais et al. 2012. PubMed ID: 23108489; Natera-de Benito et al. 2017. PubMed ID: 29054425). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular characterization of congenital myasthenic syndromes in Spain. | Natera-de Benito D | Neuromuscular disorders : NMD | 2017 | PMID: 29054425 |
| Clinical and molecular analysis of isovaleric acidemia patients in the United Arab Emirates reveals remarkable phenotypes and four novel mutations in the IVD gene. | Hertecant JL | European journal of medical genetics | 2012 | PMID: 22960500 |
| Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: a study of 680 patients. | Abicht A | Human mutation | 2012 | PMID: 22678886 |
| MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. | Cartaud A | The Journal of cell biology | 2004 | PMID: 15159418 |
| Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic). | Donger C | American journal of human genetics | 1998 | PMID: 9758617 |
Text-mined citations for rs121908923 ...
HelpThese 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 Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.