VCV000214153.79 - ClinVar

NM_001698.3(AUH):c.381A>G (p.Ile127Met)

Germline

Classification

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.

(8)

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
Uncertain significance(3); Benign(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001698.3(AUH):c.381A>G (p.Ile127Met)

Variation ID: 214153 Accession: VCV000214153.79

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q22.31 9: 91355920 (GRCh38) [ NCBI UCSC ] 9: 94118202 (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	Oct 9, 2016	Oct 20, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001698.3:c.381A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001689.1:p.Ile127Met	missense
NM_001306190.2:c.381A>G	NP_001293119.1:p.Ile127Met	missense
NM_001351431.2:c.54A>G	NP_001338360.1:p.Ile18Met	missense
NM_001351432.2:c.54A>G	NP_001338361.1:p.Ile18Met	missense
NM_001351433.2:c.54A>G	NP_001338362.1:p.Ile18Met	missense
NC_000009.12:g.91355920T>C
NC_000009.11:g.94118202T>C
NG_008017.1:g.11005A>G
LRG_449:g.11005A>G
LRG_449t1:c.381A>G	LRG_449p1:p.Ile127Met

... more HGVS ... less HGVS

Protein change

I127M, I18M

Other names

p.I127M:ATA>ATG

Canonical SPDI

NC_000009.12:91355919:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00140 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

The Genome Aggregation Database (gnomAD) 0.00125

Trans-Omics for Precision Medicine (TOPMed) 0.00137

1000 Genomes Project 0.00140

Exome Aggregation Consortium (ExAC) 0.00168

1000 Genomes Project 30x 0.00187

The Genome Aggregation Database (gnomAD), exomes 0.00201

Links

ClinGen: CA324949 dbSNP: rs146227896 VarSome

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
Gene	OMIM	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.
AUH		-	-	GRCh38 GRCh37	194	276

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.
3-methylglutaconic aciduria type 1	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 30, 2024	RCV000275240.27
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Jun 25, 2018	RCV000487826.35

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.
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	3-methylglutaconic aciduria type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000480873.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Benign (Jun 25, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000251186.13 First in ClinVar: Oct 11, 2015 Last updated: Oct 09, 2016
Uncertain significance (Dec 01, 2016)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000575581.32 First in ClinVar: May 08, 2017 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Apr 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	3-methylglutaconic aciduria type 1 Affected status: no Allele origin: germline	Elsea Laboratory, Baylor College of Medicine Accession: SCV001424186.1 First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020	Sex: male Testing laboratory: Org: 1006
Likely benign (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	3-methylglutaconic aciduria type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001014469.7 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001554200.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The AUH p.I127M variant was not identified in the literature but was identified in dbSNP (ID: rs146227896) and ClinVar (classified as uncertain significance by GeneDx, … (more) The AUH p.I127M variant was not identified in the literature but was identified in dbSNP (ID: rs146227896) and ClinVar (classified as uncertain significance by GeneDx, Illumina, CeGaT Praxis and Elsea Laboratory, Baylor College of Medicine; and as likely benign by Invitae). The variant was identified in control databases in 518 of 282744 chromosomes (5 homozygous) at a frequency of 0.001832 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I127 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036983.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002038082.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

The AUH p.I127M variant was not identified in the literature but was identified in dbSNP (ID: rs146227896) and ClinVar (classified as uncertain significance by GeneDx, Illumina, CeGaT Praxis and Elsea Laboratory, Baylor College of Medicine; and as likely benign by Invitae). The variant was identified in control databases in 518 of 282744 chromosomes (5 homozygous) at a frequency of 0.001832 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I127 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs146227896 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001698.3(AUH):c.381A>G (p.Ile127Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146227896 ...