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

dbSNP: rs1948868228

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wanghongyan lab, Fudan University	RCV001257076	SCV001190517	likely pathogenic	Brachydactyly type A1	2020-03-23	criteria provided, single submitter	clinical testing	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001573168	SCV002231551	pathogenic	not provided	2023-02-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 834083). 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. This variant is not present in population databases (gnomAD no frequency). 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.
GeneDx	RCV001573168	SCV005848250	likely pathogenic	not provided	2024-08-14	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect with a significant decrease in secreted IHH and intracellular levels of cleaved IHH (PMID: 38917024); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18629882, 32311039, 25696018, 38917024)
OMIM	RCV001257076	SCV000029642	pathogenic	Brachydactyly type A1	2008-08-15	no assertion criteria provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573168	SCV001798615	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001573168	SCV001951077	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001573168	SCV001965662	pathogenic	not provided		no assertion criteria provided	clinical testing