This variant disrupts the p.Gly15 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: 12626389, 28454995, Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of PMM2-congenital disorder of glycosylation (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553249). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 15 of the PMM2 protein (p.Gly15Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000303.3(PMM2):c.44G>C (p.Gly15Ala)
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.
(5)
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.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)
5
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000303.3(PMM2):c.44G>C (p.Gly15Ala)
Variation ID: 553249 Accession: VCV000553249.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.2 16: 8797926 (GRCh38) [ NCBI UCSC ] 16: 8891783 (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 Aug 5, 2018 Oct 26, 2024 Aug 30, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000303.3:c.44G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000294.1:p.Gly15Ala missense NC_000016.10:g.8797926G>C NC_000016.9:g.8891783G>C NG_009209.1:g.5114G>C NG_033146.1:g.4723C>G - Protein change
- G15A
- Other names
- -
- Canonical SPDI
- NC_000016.10:8797925:G:C
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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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Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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. |
|||
| PMM2 | - | - |
GRCh38 GRCh37 |
777 | 876 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Aug 30, 2024 | RCV000668655.15 |
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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|---|---|---|---|---|---|
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Uncertain significance
(Aug 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793289.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
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Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001435297.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Family history: no
Sex: male
Secondary finding: no
|
|
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Likely pathogenic
(Dec 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001214942.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Gly15 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: … (more)
This variant disrupts the p.Gly15 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: 12626389, 28454995, Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of PMM2-congenital disorder of glycosylation (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553249). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 15 of the PMM2 protein (p.Gly15Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
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Likely pathogenic
(Feb 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005056368.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Aug 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005381496.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
Variant summary: PMM2 c.44G>C (p.Gly15Ala) 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: PMM2 c.44G>C (p.Gly15Ala) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.44G>C has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (example:Baker_2019, Starosta_2021, Stranneheim_2021) . These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.43G>A, p.Gly15Arg), supporting the critical relevance of codon 15 to PMM2 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 33413482, 30577886, 33726816). ClinVar contains an entry for this variant (Variation ID: 553249). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
Comment:
Comment:
Variant summary: PMM2 c.44G>C (p.Gly15Ala) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.44G>C has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (example:Baker_2019, Starosta_2021, Stranneheim_2021) . These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.43G>A, p.Gly15Arg), supporting the critical relevance of codon 15 to PMM2 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 33413482, 30577886, 33726816). ClinVar contains an entry for this variant (Variation ID: 553249). Based on the evidence outlined above, the variant was classified 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 variant disrupts the p.Gly15 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: 12626389, 28454995, Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of PMM2-congenital disorder of glycosylation (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553249). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 15 of the PMM2 protein (p.Gly15Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
Variant summary: PMM2 c.44G>C (p.Gly15Ala) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.44G>C has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (example:Baker_2019, Starosta_2021, Stranneheim_2021) . These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.43G>A, p.Gly15Arg), supporting the critical relevance of codon 15 to PMM2 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 33413482, 30577886, 33726816). ClinVar contains an entry for this variant (Variation ID: 553249). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. | Stranneheim H | Genome medicine | 2021 | PMID: 33726816 |
| Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up. | Starosta RT | Orphanet journal of rare diseases | 2021 | PMID: 33413482 |
| Automated Clinical Exome Reanalysis Reveals Novel Diagnoses. | Baker SW | The Journal of molecular diagnostics : JMD | 2019 | PMID: 30577886 |
| A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield. | Alfares A | Molecular genetics and metabolism | 2017 | PMID: 28454995 |
| Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. | Haeuptle MA | Human mutation | 2009 | PMID: 19862844 |
| Increased fucosylation and reduced branching of serum glycoprotein N-glycans in all known subtypes of congenital disorder of glycosylation I. | Callewaert N | Glycobiology | 2003 | PMID: 12626389 |
Text-mined citations for rs958073558 ...
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 27, 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.