ClinVar Genomic variation as it relates to human health
NM_000057.4(BLM):c.3164G>C (p.Cys1055Ser)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000057.4(BLM):c.3164G>C (p.Cys1055Ser)
Variation ID: 42078 Accession: VCV000042078.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 90794311 (GRCh38) [ NCBI UCSC ] 15: 91337541 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 3, 2013 May 1, 2024 Feb 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000057.4:c.3164G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000048.1:p.Cys1055Ser missense NM_001287246.2:c.3164G>C NP_001274175.1:p.Cys1055Ser missense NM_001287247.2:c.3164G>C NP_001274176.1:p.Cys1055Ser missense NM_001287248.2:c.2039G>C NP_001274177.1:p.Cys680Ser missense NC_000015.10:g.90794311G>C NC_000015.9:g.91337541G>C NG_007272.1:g.81940G>C LRG_20:g.81940G>C LRG_20t1:c.3164G>C P54132:p.Cys1055Ser - Protein change
- C1055S, C680S
- Other names
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- Canonical SPDI
- NC_000015.10:90794310:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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BLM | - | - |
GRCh38 GRCh37 |
4288 | 4339 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV000034904.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 14, 2024 | RCV000569697.5 |
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
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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
(-)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001426546.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
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Pathogenic
(Oct 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002787346.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004210906.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000749572.8
First in ClinVar: May 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1055 of the BLM protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1055 of the BLM protein (p.Cys1055Ser). This variant is present in population databases (rs367543029, gnomAD 0.002%). This missense change has been observed in individuals with Bloom syndrome (PMID: 7585968, 17407155, 35218564). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42078). 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 BLM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BLM function (PMID: 9840919, 10069810, 11399766, 28877996). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000672962.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.C1055S pathogenic mutation (also known as c.3164G>C), located in coding exon 15 of the BLM gene, results from a G to C substitution at … (more)
The p.C1055S pathogenic mutation (also known as c.3164G>C), located in coding exon 15 of the BLM gene, results from a G to C substitution at nucleotide position 3164. The cysteine at codon 1055 is replaced by serine, an amino acid with dissimilar properties. This mutation has been reported in the literature in both a homozygous and compound heterozygous state in individuals with Bloom syndrome (Ellis NA et al. Cell, 1995 Nov;83:655-66; German J et al. Hum. Mutat., 2007 Aug;28:743-53; Montenegro MM et al. Mol Genet Genomic Med, 2020 04;8:e1133). Functional studies have also demonstrated that this alteration causes reduced BLM protein expression and lacks detectable helicase and DNA-dependent ATPase activities, which are essential for wild-type interaction of BLM with tp53 in the DNA damage response pathway (Wang XW et al. J. Biol. Chem., 2001 Aug;276:32948-55; Neff NF et al. Mol. Biol. Cell, 1999 Mar;10:665-76). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139712.1
First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020 |
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Pathogenic
(Jul 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918657.2
First in ClinVar: Jun 02, 2019 Last updated: Aug 09, 2020 |
Comment:
Variant summary: BLM c.3164G>C (p.Cys1055Ser) results in a non-conservative amino acid change located in the ATP-dependent DNA helicase RecQ, zinc-binding domain of the encoded protein … (more)
Variant summary: BLM c.3164G>C (p.Cys1055Ser) results in a non-conservative amino acid change located in the ATP-dependent DNA helicase RecQ, zinc-binding domain of 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 8e-06 in 248860 control chromosomes. c.3164G>C has been reported in the literature in multiple individuals affected with Bloom Syndrome (example, Ellis_1995, German_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal helicase and DNA dependent ATPase activities (Neff_1999). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Bloom syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018395.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530061.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BLM c.3164G>C (p.C1055S) variant has been reported as homozygous and compound heterozygous in several individuals with Bloom syndrome (PMID: 7585968, 17407155, 32073752, 32860008). Functional … (more)
The BLM c.3164G>C (p.C1055S) variant has been reported as homozygous and compound heterozygous in several individuals with Bloom syndrome (PMID: 7585968, 17407155, 32073752, 32860008). Functional studies have shown that this variant significantly reduces the helicase and ATPase enzymatic activities of the BLM protein, and causes defective nuclear body formation and localization (PMID: 9840919, 10069810, 11399766). This variant was observed in 2/112908 chromosomes in the Non-Finnish European population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 42078). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Phenotypic spectrum of BLM- and RMI1-related Bloom syndrome. | Gönenc II | Clinical genetics | 2022 | PMID: 35218564 |
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
Gene expression profile suggesting immunological dysregulation in two Brazilian Bloom's syndrome cases. | Montenegro MM | Molecular genetics & genomic medicine | 2020 | PMID: 32073752 |
BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres. | Sobinoff AP | The EMBO journal | 2017 | PMID: 28877996 |
DNA helicases associated with genetic instability, cancer, and aging. | Suhasini AN | Advances in experimental medicine and biology | 2013 | PMID: 23161009 |
Non-Bloom syndrome-associated partial and total loss-of-function variants of BLM helicase. | Mirzaei H | Proceedings of the National Academy of Sciences of the United States of America | 2012 | PMID: 23129629 |
Helicase-inactivating mutations as a basis for dominant negative phenotypes. | Wu Y | Cell cycle (Georgetown, Tex.) | 2010 | PMID: 20980836 |
Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry. | German J | Human mutation | 2007 | PMID: 17407155 |
Functional interaction of p53 and BLM DNA helicase in apoptosis. | Wang XW | The Journal of biological chemistry | 2001 | PMID: 11399766 |
The DNA helicase activity of BLM is necessary for the correction of the genomic instability of bloom syndrome cells. | Neff NF | Molecular biology of the cell | 1999 | PMID: 10069810 |
Point mutations causing Bloom's syndrome abolish ATPase and DNA helicase activities of the BLM protein. | Bahr A | Oncogene | 1998 | PMID: 9840919 |
The Ashkenazic Jewish Bloom syndrome mutation blmAsh is present in non-Jewish Americans of Spanish ancestry. | Ellis NA | American journal of human genetics | 1998 | PMID: 9837821 |
The Bloom's syndrome gene product is homologous to RecQ helicases. | Ellis NA | Cell | 1995 | PMID: 7585968 |
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Text-mined citations for rs367543029 ...
HelpRecord last updated May 08, 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.