Published functional studies demonstrate a damaging effect with significant loss of enzyme activity for the R228C mutant at 9% of the wild-type activity (Rizzo et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16476818, 10577908, 30925032, 31456290, 16837225, 28257279, 28471629, 25047030, 27717089, 32395410)
ClinVar Genomic variation as it relates to human health
NM_000382.3(ALDH3A2):c.682C>T (p.Arg228Cys)
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/Likely 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_000382.3(ALDH3A2):c.682C>T (p.Arg228Cys)
Variation ID: 556574 Accession: VCV000556574.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p11.2 17: 19657746 (GRCh38) [ NCBI UCSC ] 17: 19561059 (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 Feb 14, 2024 Oct 14, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000382.3:c.682C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000373.1:p.Arg228Cys missense NM_001031806.2:c.682C>T NP_001026976.1:p.Arg228Cys missense NM_001369136.1:c.682C>T NP_001356065.1:p.Arg228Cys missense NM_001369137.2:c.682C>T NP_001356066.1:p.Arg228Cys missense NM_001369138.2:c.682C>T NP_001356067.1:p.Arg228Cys missense NM_001369139.1:c.682C>T NP_001356068.1:p.Arg228Cys missense NM_001369146.2:c.682C>T NP_001356075.1:p.Arg228Cys missense NM_001369148.2:c.103C>T NP_001356077.1:p.Arg35Cys missense NC_000017.11:g.19657746C>T NC_000017.10:g.19561059C>T NG_007095.2:g.13996C>T - Protein change
- R228C, R35C
- Other names
- -
- Canonical SPDI
- NC_000017.11:19657745:C:T
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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. |
|||
| ALDH3A2 | - | - |
GRCh38 GRCh37 |
637 | 759 | |
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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 10, 2022 | RCV000672596.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 14, 2023 | RCV001383429.7 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Feb 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000797711.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Pathogenic
(Jan 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002775173.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Mar 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799962.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
|
|
|
Pathogenic
(Feb 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002099564.2
First in ClinVar: Mar 04, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with significant loss of enzyme activity for the R228C mutant at 9% of the wild-type activity (Rizzo et … (more)
Published functional studies demonstrate a damaging effect with significant loss of enzyme activity for the R228C mutant at 9% of the wild-type activity (Rizzo et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16476818, 10577908, 30925032, 31456290, 16837225, 28257279, 28471629, 25047030, 27717089, 32395410) (less)
|
|
|
Pathogenic
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001582570.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 228 of the ALDH3A2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 228 of the ALDH3A2 protein (p.Arg228Cys). This variant is present in population databases (rs72547566, gnomAD 0.003%). This missense change has been observed in individuals with Sjögren–Larsson syndrome (PMID: 10577908, 27717089, 28257279, 28471629, 30925032). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 556574). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ALDH3A2 function (PMID: 10577908). This variant disrupts the p.Arg228 amino acid residue in ALDH3A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22397046, 29704247). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jun 23, 2019)
|
no assertion criteria provided
Method: research
|
Sjögren-Larsson syndrome
Affected status: yes
Allele origin:
inherited
|
Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001160895.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
|
|
|
Pathogenic
(Aug 02, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Sjögren-Larsson syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002093179.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 228 of the ALDH3A2 protein (p.Arg228Cys). This variant is present in population databases (rs72547566, gnomAD 0.003%). This missense change has been observed in individuals with Sjögren–Larsson syndrome (PMID: 10577908, 27717089, 28257279, 28471629, 30925032). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 556574). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ALDH3A2 function (PMID: 10577908). This variant disrupts the p.Arg228 amino acid residue in ALDH3A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22397046, 29704247). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been 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:
Published functional studies demonstrate a damaging effect with significant loss of enzyme activity for the R228C mutant at 9% of the wild-type activity (Rizzo et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16476818, 10577908, 30925032, 31456290, 16837225, 28257279, 28471629, 25047030, 27717089, 32395410)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 228 of the ALDH3A2 protein (p.Arg228Cys). This variant is present in population databases (rs72547566, gnomAD 0.003%). This missense change has been observed in individuals with Sjögren–Larsson syndrome (PMID: 10577908, 27717089, 28257279, 28471629, 30925032). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 556574). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ALDH3A2 function (PMID: 10577908). This variant disrupts the p.Arg228 amino acid residue in ALDH3A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22397046, 29704247). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies. | Abu Diab A | Acta ophthalmologica | 2019 | PMID: 30925032 |
| Clinical and molecular characterization and response to acitretin in three families with Sjögren-Larsson syndrome. | Vural S | International journal of dermatology | 2018 | PMID: 29704247 |
| Intrathecal Baclofen Therapy for the Treatment of Spasticity in Sjögren-Larsson Syndrome. | Hidalgo ET | Journal of child neurology | 2017 | PMID: 28257279 |
| Chromosomal microarray in a highly consanguineous population: diagnostic yield, utility of regions of homozygosity, and novel mutations. | Alabdullatif MA | Clinical genetics | 2017 | PMID: 27717089 |
| Coexistence of Two Rare Autosomal Recessive Disorders: Activation-Induced Cytidine Deaminase Deficiency and Sjogren-Larsson Syndrome. | Shamriz O | The Israel Medical Association journal : IMAJ | 2016 | PMID: 28471629 |
| A gatekeeper helix determines the substrate specificity of Sjögren-Larsson Syndrome enzyme fatty aldehyde dehydrogenase. | Keller MA | Nature communications | 2014 | PMID: 25047030 |
| Sjögren-Larsson syndrome: report of monozygote twins and a case with a novel mutation. | Yiş U | The Turkish journal of pediatrics | 2012 | PMID: 22397046 |
| Bezafibrate induces FALDH in human fibroblasts; implications for Sjögren-Larsson syndrome. | Gloerich J | Molecular genetics and metabolism | 2006 | PMID: 16837225 |
| The molecular basis of Sjögren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene. | Rizzo WB | American journal of human genetics | 1999 | PMID: 10577908 |
Text-mined citations for rs72547566 ...
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 Sep 29, 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.