Submissions for variant NM_000142.5(FGFR3):c.1949A>T (p.Lys650Met)

dbSNP: rs121913105

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001574416	SCV001801232	pathogenic	not provided	2020-07-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate significantly increased receptor kinase activity compared to wild type (Tavormina et al., 1999; Krejci et al., 2008); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10053006, 30782830, 18076102, 9207791, 27214123, 10671061, 25119967, 19088846, 19039991, 25614871, 9857065, 10377013, 29242050, 29030113, 29360984, 22045636, 20301540, 30048571, 29542187, 30168875, 29068064)
Blueprint Genetics	RCV001574416	SCV001832244	pathogenic	not provided	2018-02-05	criteria provided, single submitter	clinical testing
Invitae	RCV001574416	SCV002507707	pathogenic	not provided	2022-07-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys650 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17875876, 26818779). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 9857065, 19088846). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16341). This missense change has been observed in individual(s) with severe achondroplasia with developmental delay and acanthosis nigricans (PMID: 10053006, 18076102). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 650 of the FGFR3 protein (p.Lys650Met).
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV002310592	SCV002601621	pathogenic	Hypochondroplasia	2022-09-29	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 14 of the FGFR3 gene that results in the amino acid substitution of Methionine for Lysine at codon 650 was detected . The p.Lys650Met variant has not been reported in the 1000 genomes, gnomAD and our internal databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496392	SCV002808080	pathogenic	Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Colorectal cancer; Germ cell tumor of testis	2022-05-31	criteria provided, single submitter	clinical testing
OMIM	RCV000017749	SCV000038027	pathogenic	SEVERE ACHONDRODYSPLASIA WITH DEVELOPMENTAL DELAY AND ACANTHOSIS NIGRICANS	2008-01-15	no assertion criteria provided	literature only
OMIM	RCV000017750	SCV000038028	pathogenic	Thanatophoric dysplasia type 1	2008-01-15	no assertion criteria provided	literature only
GeneReviews	RCV000017750	SCV000086709	not provided	Thanatophoric dysplasia type 1		no assertion provided	literature only