ClinVar Genomic variation as it relates to human health
NM_000687.4(AHCY):c.428A>G (p.Tyr143Cys)
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_000687.4(AHCY):c.428A>G (p.Tyr143Cys)
Variation ID: 12953 Accession: VCV000012953.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q11.22 20: 34292375 (GRCh38) [ NCBI UCSC ] 20: 32880181 (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 Feb 7, 2015 Mar 10, 2024 Aug 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000687.4:c.428A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000678.1:p.Tyr143Cys missense NM_001161766.2:c.344A>G NP_001155238.1:p.Tyr115Cys missense NM_001322084.2:c.344A>G NP_001309013.1:p.Tyr115Cys missense NM_001322085.2:c.344A>G NP_001309014.1:p.Tyr115Cys missense NM_001322086.2:c.434A>G NP_001309015.1:p.Tyr145Cys missense NM_001362750.2:c.428A>G NP_001349679.1:p.Tyr143Cys missense NC_000020.11:g.34292375T>C NC_000020.10:g.32880181T>C NG_012630.2:g.24428A>G - Protein change
- Y143C, Y115C, Y145C
- Other names
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- Canonical SPDI
- NC_000020.11:34292374:T: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.
The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
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
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. |
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AHCY | - | - |
GRCh38 GRCh37 |
269 | 294 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 25, 2023 | RCV000013819.34 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 10, 2023 | RCV000224240.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2017 | RCV000624639.3 | |
Likely pathogenic (1) |
no assertion criteria provided
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Aug 5, 2017 | RCV000662292.1 |
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
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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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Likely pathogenic
(Jul 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002107213.3
First in ClinVar: Mar 28, 2022 Last updated: Jul 16, 2023 |
Comment:
Published functional studies of enzymatic assays showed that this variant reduced hydrolysis and synthesis to 25% and 34% of wildtype, suggesting a damaging effect (Beluzic … (more)
Published functional studies of enzymatic assays showed that this variant reduced hydrolysis and synthesis to 25% and 34% of wildtype, suggesting a damaging effect (Beluzic et al., 2006); 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: 28647132, 34426522, 31589614, 28779239, 15024124, 18211827, 16736098, 33072517, 26095522, 16872278, 35463910) (less)
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Pathogenic
(Jun 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020741.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: AHCY c.428A>G (p.Tyr143Cys) 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: AHCY c.428A>G (p.Tyr143Cys) 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 8e-05 in 250902 control chromosomes (gnomAD). c.428A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (e.g. Baric_2004, Baric_2005, Buist_2006), as well as in individuals affected with Neurodevelopmental Disorders (Soden_2014) and Rhabdomyolysis (Vivante_2017), which are associated phenotypes for Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase. These data indicate that the variant is very likely to be associated with disease. Recombinant proteins purified from E.coli cultures showed the variant had reduced hydrolysis activity (25%) and reduced synthesis activity (34%) as compared to wild-type (Beluzic_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16435181, 15024124, 16872278, 16736098, 25473036, 28779239). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 19, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281169.2
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446643.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Myopathy (present)
Sex: female
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Likely pathogenic
(Apr 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002787888.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742929.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003459718.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs121918608, gnomAD 0.02%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral … (more)
This variant is present in population databases (rs121918608, gnomAD 0.02%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 143 of the AHCY protein (p.Tyr143Cys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AHCY function (PMID: 16872278). 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 AHCY protein function. This missense change has been observed in individual(s) with clinical features of S-adenosylhomocysteine hydrolase deficiency (PMID: 15024124, 16736098, 28779239, 33072517). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12953). (less)
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Likely pathogenic
(Aug 05, 2017)
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no assertion criteria provided
Method: literature only
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Rhabdomyolysis
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Accession: SCV000784620.1
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
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Pathogenic
(Mar 23, 2004)
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no assertion criteria provided
Method: literature only
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HYPERMETHIONINEMIA WITH S-ADENOSYLHOMOCYSTEINE HYDROLASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034066.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
For discussion of the tyr143-to-cys (Y143C) mutation in the AHCY gene that was found in compound heterozygous state in a patient with hypermethioninemia with S-adenosylhomocysteine … (more)
For discussion of the tyr143-to-cys (Y143C) mutation in the AHCY gene that was found in compound heterozygous state in a patient with hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (613752) by Baric et al. (2004), see 180960.0001. (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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The diagnosis of inborn errors of metabolism in previously undiagnosed adults referred for medical genetics evaluation. | Lee KN | Molecular genetics and metabolism reports | 2020 | PMID: 33072517 |
Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases. | Vivante A | Pediatric nephrology (Berlin, Germany) | 2017 | PMID: 28779239 |
Mutations in S-adenosylhomocysteine hydrolase (AHCY) affect its nucleocytoplasmic distribution and capability to interact with S-adenosylhomocysteine hydrolase-like 1 protein. | Grbeša I | European journal of cell biology | 2017 | PMID: 28647132 |
Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. | Soden SE | Science translational medicine | 2014 | PMID: 25473036 |
S-Adenosylhomocysteine hydrolase (AdoHcyase) deficiency: enzymatic capabilities of human AdoHcyase are highly effected by changes to codon 89 and its surrounding residues. | Beluzić R | Biochemical and biophysical research communications | 2008 | PMID: 18211827 |
A single mutation at Tyr143 of human S-adenosylhomocysteine hydrolase renders the enzyme thermosensitive and affects the oxidation state of bound cofactor nicotinamide-adenine dinucleotide. | Beluzić R | The Biochemical journal | 2006 | PMID: 16872278 |
S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man. | Buist NR | Journal of inherited metabolic disease | 2006 | PMID: 16736098 |
S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy. | Barić I | Journal of inherited metabolic disease | 2005 | PMID: 16435181 |
S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. | Baric I | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15024124 |
Text-mined citations for rs121918608 ...
HelpRecord last updated Mar 11, 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.