NM_001174147.2(LMX1B):c.226T>G (p.Trp76Gly) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 20, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000421725.6

Allele description [Variation Report for NM_001174147.2(LMX1B):c.226T>G (p.Trp76Gly)]

NM_001174147.2(LMX1B):c.226T>G (p.Trp76Gly)

Gene:

LMX1B:LIM homeobox transcription factor 1 beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q33.3

Genomic location:

Preferred name:

NM_001174147.2(LMX1B):c.226T>G (p.Trp76Gly)

HGVS:

NC_000009.12:g.126615469T>G
NG_017039.1:g.6027T>G
NM_001174146.2:c.226T>G
NM_001174147.2:c.226T>GMANE SELECT
NM_002316.4:c.226T>G
NP_001167617.1:p.Trp76Gly
NP_001167618.1:p.Trp76Gly
NP_002307.2:p.Trp76Gly
NP_002307.2:p.Trp76Gly
LRG_1014t1:c.226T>G
LRG_1014t2:c.226T>G
LRG_1014t3:c.226T>G
LRG_1014:g.6027T>G
LRG_1014p1:p.Trp76Gly
LRG_1014p2:p.Trp76Gly
LRG_1014p3:p.Trp76Gly
NC_000009.11:g.129377748T>G
NM_002316.3:c.226T>G

Protein change:

W76G

Links:

dbSNP: rs1057520783

NCBI 1000 Genomes Browser:

rs1057520783

Molecular consequence:

NM_001174146.2:c.226T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001174147.2:c.226T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002316.4:c.226T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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conserved hypothetical protein - lantibiotic associated [Streptococcus pyogenes ...
conserved hypothetical protein - lantibiotic associated [Streptococcus pyogenes M1 GAS]
gi|13622229|gb|AAK33969.1||gnl|uohs 1086

Protein
NADH dehydrogenase subunit G [Paraburkholderia xenovorans LB400]
NADH dehydrogenase subunit G [Paraburkholderia xenovorans LB400]
gi|91686572|gnl|jgi|Bxe_A3208|gb|AB 2.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000517431	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Sep 7, 2016)	germline	clinical testing	Citation Link,
SCV002154268	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 20, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15498463, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000517431

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Sep 7, 2016)

germline

clinical testing

Citation Link,

SCV002154268

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 20, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

The human LMX1B gene: transcription unit, promoter, and pathogenic mutations.

Dunston JA, Hamlington JD, Zaveri J, Sweeney E, Sibbring J, Tran C, Malbroux M, O'Neill JP, Mountford R, McIntosh I.

Genomics. 2004 Sep;84(3):565-76.

PubMed [citation]

PMID:: 15498463

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

Details of each submission

From GeneDx, SCV000517431.3

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

Description

The W76G variant in the LMX1B gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The W76G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W76G variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the first LIM zinc-binding domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (W76R) has been reported in association with nail patella syndrome (Dunston et al., 2004). We interpret W76G as a likely pathogenic variant

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002154268.3

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

Description

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. This variant disrupts the p.Trp76 amino acid residue in LMX1B. Other variant(s) that disrupt this residue have been observed in individuals with LMX1B-related conditions (PMID: 15498463; 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 379916). This missense change has been observed in individual(s) with clinical features of nail-patella syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with glycine at codon 76 of the LMX1B protein (p.Trp76Gly). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and glycine.

#	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

Last Updated: Sep 29, 2024

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