VCV000007004.5 - ClinVar

NM_001174147.2(LMX1B):c.303_304del (p.Tyr102fs)

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.

(3)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001174147.2(LMX1B):c.303_304del (p.Tyr102fs)

Variation ID: 7004 Accession: VCV000007004.5

Type and length

Deletion, 2 bp

Location

Cytogenetic: 9q33.3 9: 126615545-126615546 (GRCh38) [ NCBI UCSC ] 9: 129377824-129377825 (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	Apr 4, 2013	Feb 14, 2024	Oct 7, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001174147.2:c.303_304del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001167618.1:p.Tyr102fs	frameshift
NM_001174146.2:c.303_304del	NP_001167617.1:p.Tyr102fs	frameshift
NM_002316.3:c.303_304del
NM_002316.4:c.303_304del	NP_002307.2:p.Tyr102fs	frameshift
NC_000009.12:g.126615546_126615547del
NC_000009.11:g.129377825_129377826del
NG_017039.1:g.6104_6105del
LRG_1014:g.6104_6105del
LRG_1014t1:c.303_304del	LRG_1014p1:p.Tyr102fs
LRG_1014t2:c.303_304del	LRG_1014p2:p.Tyr102fs
LRG_1014t3:c.303_304del	LRG_1014p3:p.Tyr102fs

... more HGVS ... less HGVS

Protein change

Y102fs

Other names

Canonical SPDI

NC_000009.12:126615544:TGT:T

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.

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

Links

OMIM: 602575.0005 VarSome

Comment on variant

NCBI staff provided an HGVS expression for allelic variant 602575.0005 from the sequence reported in Figure 1 of the paper by Vollrath et al., 1998 (PubMed 9618165).

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.
LMX1B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	592	633

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.
Nail-patella syndrome	Pathogenic (1)	no assertion criteria provided	Jul 1, 1998	RCV000007419.3
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 7, 2022	RCV002512873.4

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.
Pathogenic (Oct 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003441483.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 9618165‚ 25898926‚ 9590287‚ 15498463 Comment: For these reasons, this variant has been classified as Pathogenic. This variant is also known as 233delTG or c.234_235delGT. This premature translational stop signal has … (more) For these reasons, this variant has been classified as Pathogenic. This variant is also known as 233delTG or c.234_235delGT. This premature translational stop signal has been observed in individual(s) with nail-patella syndrome (PMID: 9618165, 25898926). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Tyr102Leufs*45) in the LMX1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMX1B are known to be pathogenic (PMID: 9590287, 15498463). (less)
Pathogenic (Sep 19, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003842873.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as 233delTG due to use of alternate nomenclature; This variant is associated with the following publications: (PMID: 9618165) (less)
Pathogenic (Jul 01, 1998)	no assertion criteria provided Method: literature only	NAIL-PATELLA SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027619.2 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2020	Publications: PubMed (1) PubMed: 9618165 Comment on evidence: In a 4-generation family (UM:65) of French and Irish ancestry, Vollrath et al. (1998) found that the proband and 6 other individuals with glaucoma also … (more) In a 4-generation family (UM:65) of French and Irish ancestry, Vollrath et al. (1998) found that the proband and 6 other individuals with glaucoma also had nail-patella syndrome (NPS; 161200). Age at onset of glaucoma ranged from birth to 54 years (mean, 24 years). Proteinuria was not found in family members who were screened, but medical records indicated that the proband's mother had proteinuria and kidney disease. The proband of family UM:65 was heterozygous for a 2-bp deletion in exon 2 (233delTG) of the LMX1B gene, predicting a severely truncated protein that lacks part of the LIM1 domain and all of the LIM2 and homeodomains, and contains a stretch of 44 N-terminal amino acid residues generated from an incorrect reading frame. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant is also known as 233delTG or c.234_235delGT. This premature translational stop signal has been observed in individual(s) with nail-patella syndrome (PMID: 9618165, 25898926). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Tyr102Leufs*45) in the LMX1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMX1B are known to be pathogenic (PMID: 9590287, 15498463).

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as 233delTG due to use of alternate nomenclature; This variant is associated with the following publications: (PMID: 9618165)

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

Title	Author	Journal	Year	Link
Nail-Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity.	Ghoumid J	European journal of human genetics : EJHG	2016	PMID: 25898926
The human LMX1B gene: transcription unit, promoter, and pathogenic mutations.	Dunston JA	Genomics	2004	PMID: 15498463
Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome.	Vollrath D	Human molecular genetics	1998	PMID: 9618165
Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome.	Dreyer SD	Nature genetics	1998	PMID: 9590287

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001174147.2(LMX1B):c.303_304del (p.Tyr102fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...