Submissions for variant NM_000142.5(FGFR3):c.1619A>C (p.Asn540Thr)

dbSNP: rs77722678

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001549822	SCV001770044	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25728633, 9452043, 30048571, 30681580, 35438268)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001549822	SCV002507644	likely pathogenic	not provided	2020-06-03	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of autosomal dominant hypochondroplasia (PMID: 9452043, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1658A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 16344). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asn540 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7670477, 8589686, 9452043, 25614871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 540 of the FGFR3 protein (p.Asn540Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000017753	SCV005375364	likely pathogenic	Hypochondroplasia		criteria provided, single submitter	not provided
OMIM	RCV000017753	SCV000038031	pathogenic	Hypochondroplasia	1998-01-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001549822	SCV002037525	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001549822	SCV002037932	pathogenic	not provided		no assertion criteria provided	clinical testing