NM_000463.3(UGT1A1):c.1231G>T (p.Val411Leu) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Aug 25, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000731958.18

Allele description [Variation Report for NM_000463.3(UGT1A1):c.1231G>T (p.Val411Leu)]

NM_000463.3(UGT1A1):c.1231G>T (p.Val411Leu)

Genes:

UGT1A:UDP glucuronosyltransferase family 1 member A complex locus [Gene - HGNC]
UGT1A10:UDP glucuronosyltransferase family 1 member A10 [Gene - OMIM - HGNC]
UGT1A1:UDP glucuronosyltransferase family 1 member A1 [Gene - OMIM - HGNC]
UGT1A3:UDP glucuronosyltransferase family 1 member A3 [Gene - OMIM - HGNC]
UGT1A4:UDP glucuronosyltransferase family 1 member A4 [Gene - OMIM - HGNC]
UGT1A5:UDP glucuronosyltransferase family 1 member A5 [Gene - OMIM - HGNC]
UGT1A6:UDP glucuronosyltransferase family 1 member A6 [Gene - OMIM - HGNC]
UGT1A7:UDP glucuronosyltransferase family 1 member A7 [Gene - OMIM - HGNC]
UGT1A8:UDP glucuronosyltransferase family 1 member A8 [Gene - OMIM - HGNC]
UGT1A9:UDP glucuronosyltransferase family 1 member A9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q37.1

Genomic location:

Preferred name:

NM_000463.3(UGT1A1):c.1231G>T (p.Val411Leu)

Other names:

p.Val411Leu

HGVS:

NC_000002.12:g.233768366G>T
NG_002601.2:g.183623G>T
NG_033238.1:g.13094G>T
NM_000463.3:c.1231G>TMANE SELECT
NM_001072.4:c.1228G>TMANE SELECT
NM_007120.3:c.1234G>TMANE SELECT
NM_019075.4:c.1222G>TMANE SELECT
NM_019076.5:c.1222G>TMANE SELECT
NM_019077.3:c.1222G>TMANE SELECT
NM_019078.2:c.1234G>TMANE SELECT
NM_019093.4:c.1234G>TMANE SELECT
NM_021027.3:c.1222G>TMANE SELECT
NM_205862.3:c.427G>T
NP_000454.1:p.Val411Leu
NP_000454.1:p.Val411Leu
NP_001063.2:p.Val410Leu
NP_009051.1:p.Val412Leu
NP_061948.1:p.Val408Leu
NP_061949.3:p.Val408Leu
NP_061950.2:p.Val408Leu
NP_061951.1:p.Val412Leu
NP_061966.1:p.Val412Leu
NP_066307.1:p.Val408Leu
NP_995584.1:p.Val143Leu
LRG_733t1:c.1231G>T
LRG_733:g.13094G>T
LRG_733p1:p.Val411Leu
NC_000002.11:g.234677012G>T
NM_000463.2:c.1231G>T

Protein change:

V143L

Links:

dbSNP: rs36076514

NCBI 1000 Genomes Browser:

rs36076514

Molecular consequence:

NM_000463.3:c.1231G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001072.4:c.1228G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007120.3:c.1234G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_019075.4:c.1222G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_019076.5:c.1222G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_019077.3:c.1222G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_019078.2:c.1234G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_019093.4:c.1234G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_021027.3:c.1222G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_205862.3:c.427G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000859831	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Aug 30, 2018)	germline	clinical testing	Citation Link,
SCV001158251	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Aug 25, 2023)	germline	clinical testing	Citation Link,
SCV003259317	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004226027	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23875061, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	8	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Meta-analysis diagnostic accuracy of SNP-based pathogenicity detection tools: a case of UTG1A1 gene mutations.

Galehdari H, Saki N, Mohammadi-Asl J, Rahim F.

Int J Mol Epidemiol Genet. 2013 Jun 25;4(2):77-85. Print 2013.

PubMed [citation]

PMID:: 23875061
PMCID:: PMC3709112

See all PubMed Citations (3)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000859831.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158251.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The UGT1A1 c.1231G>T; p.Val411Leu variant (rs36076514), to our knowledge, is not reported in the medical literature, but is reported in ClinVar (Variation ID: 160230). This variant is found predominantly in the Latino/Admixed American population with an allele frequency of 0.17% (61/35,436 alleles) in the Genome Aggregation Database. The valine at codon 411 is moderately conserved, and computational analyses predict that this variant is tolerated (REVEL: 0.029). Due to limited information, the clinical significance of this variant is uncertain at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003259317.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 411 of the UGT1A1 protein (p.Val411Leu). This variant is present in population databases (rs36076514, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with UGT1A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 160230). 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 UGT1A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004226027.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (2)

Description

BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		6	not provided	not provided	not provided

Last Updated: Jun 9, 2024

ClinVar

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