VCV000834083.12 - ClinVar

NM_002181.4(IHH):c.280GAG[1] (p.Glu95del)

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.

(6)

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/Likely 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_002181.4(IHH):c.280GAG[1] (p.Glu95del)

Variation ID: 834083 Accession: VCV000834083.12

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 2q35 2: 219060183-219060185 (GRCh38) [ NCBI UCSC ] 2: 219924905-219924907 (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	Sep 27, 2020	May 12, 2024	Feb 3, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002181.4:c.280GAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002172.2:p.Glu95del	inframe deletion
NC_000002.12:g.219060183CTC[1]
NC_000002.11:g.219924905CTC[1]
NG_016741.1:g.5329GAG[1]

Protein change

E95del

Other names

Canonical SPDI

NC_000002.12:219060182:CTCCTC:CTC

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: 600726.0009 dbSNP: rs1948868228 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.
IHH		-	-	GRCh38 GRCh37	263	295

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.
Brachydactyly type A1	Likely pathogenic (2)	criteria provided, single submitter	Mar 23, 2020	RCV001257076.3
not provided	Pathogenic (4)	criteria provided, single submitter	Feb 3, 2023	RCV001573168.10

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.
Likely pathogenic (Mar 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Brachydactyly type A1 (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal, unknown	Wanghongyan lab, Fudan University Accession: SCV001190517.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020	Publications: PubMed (1) PubMed: 11455389 Comment: The p.Glu95del in IHH has been reported in 1 Dutch family (five affected family members, five unaffected family members )( Lodder 2008). We discovered this … (more) The p.Glu95del in IHH has been reported in 1 Dutch family (five affected family members, five unaffected family members )( Lodder 2008). We discovered this recurrent variant in one family from a Chinese cohort contains 1135 unrelated short stature patients. This proband and her affected father presented with the typical phenotype of BDA1(MIM 112500). Their phenotypes were similar to that of the reported cases. This variant was absent from ExAC, 1000 Genomes data, and 592 Chinese controls. The p.Glu95del was classified as "Likely Pathogenic" using the ACMG/AMP standards(PM1+PM2+PM4+PP4+PP1+PS4_PP). (less) Observation 1: Clinical Features: Thin proximal phalanges with broad epiphyses of the hand (present) , Disproportionate short stature (present) , Delayed skeletal maturation (present) , Brachydactyly type A1 (present) … (more) Thin proximal phalanges with broad epiphyses of the hand (present) , Disproportionate short stature (present) , Delayed skeletal maturation (present) , Brachydactyly type A1 (present) , Broad palm (present) , Clinodactyly of the 5th finger (present) , Clinodactyly of the 4th finger (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: Chinese Geographic origin: China Method: NGS was performed according to the manufacturer's instruction for target capturing. Captured regions were sequenced by HiSeq 2000 (Illumina, San Diego, CA, USA) and aligned to the GRCh37/hg19 human reference sequence. Variants were annotated by GATK and filtered by Ingenuity Pathway Analysis (https://variants.ingenuity.com) and TGex (http://tgex.genecards.cn/). Variants were classified following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) standards and guidelines. The identified candidate variants were confirmed by Sanger sequencing. Observation 2: Clinical Features: Cone-shaped epiphysis of the distal phalanx of the 5th finger (present) , Broad palm (present) , Disproportionate short stature (present) , Brachydactyly type A1 (present) Age: 30-39 years Sex: male Ethnicity/Population group: Chinese Geographic origin: China
Pathogenic (Feb 03, 2023)	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: SCV002231551.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 18629882‚ 32311039 Comment: This variant, c.283_285del, results in the deletion of 1 amino acid(s) of the IHH protein (p.Glu95del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.283_285del, results in the deletion of 1 amino acid(s) of the IHH protein (p.Glu95del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with brachydactyly (PMID: 18629882, 32311039). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 834083). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 15, 2008)	no assertion criteria provided Method: literature only	BRACHYDACTYLY, TYPE A1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029642.3 First in ClinVar: Apr 04, 2013 Last updated: May 12, 2024	Publications: PubMed (1) PubMed: 18629882 Comment on evidence: In affected members of a Dutch family with mild brachydactyly type A1 (BDA1; 112500), Lodder et al. (2008) identified a heterozygous 3-bp deletion (283delGAG) in … (more) In affected members of a Dutch family with mild brachydactyly type A1 (BDA1; 112500), Lodder et al. (2008) identified a heterozygous 3-bp deletion (283delGAG) in the IHH gene, resulting in an in-frame deletion of residue glu95, which was predicted to be located on the edge of a groove important for the interaction between IHH and PTCH1 (601309). Lodder et al. (2008) noted that this was the first reported deletion in the IHH gene, but that this residue has been reported to be affected in other patients with the disorder (see, e.g., E95K; 600726.0001). (less)
Pathogenic (-)	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) Study: VKGL Data-share Consensus Accession: SCV001798615.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951077.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	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: SCV001965662.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021

Comment:

The p.Glu95del in IHH has been reported in 1 Dutch family (five affected family members, five unaffected family members )( Lodder 2008). We discovered this recurrent variant in one family from a Chinese cohort contains 1135 unrelated short stature patients. This proband and her affected father presented with the typical phenotype of BDA1(MIM 112500). Their phenotypes were similar to that of the reported cases. This variant was absent from ExAC, 1000 Genomes data, and 592 Chinese controls. The p.Glu95del was classified as "Likely Pathogenic" using the ACMG/AMP standards(PM1+PM2+PM4+PP4+PP1+PS4_PP).

Comment:

This variant, c.283_285del, results in the deletion of 1 amino acid(s) of the IHH protein (p.Glu95del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with brachydactyly (PMID: 18629882, 32311039). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 834083). For these reasons, this variant has been classified as Pathogenic.

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
Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants.	Sentchordi-Montané L	The Journal of clinical endocrinology and metabolism	2020	PMID: 32311039
Deletion of 1 amino acid in Indian hedgehog leads to brachydactylyA1.	Lodder EM	American journal of medical genetics. Part A	2008	PMID: 18629882

Text-mined citations for rs1948868228 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_002181.4(IHH):c.280GAG[1] (p.Glu95del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1948868228 ...