Submissions for variant NM_000142.5(FGFR3):c.1619A>G (p.Asn540Ser)

gnomAD frequency: 0.00002  dbSNP: rs77722678

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623459	SCV000741473	uncertain significance	Inborn genetic diseases	2016-04-25	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269614	SCV001449719	pathogenic	not provided	2018-03-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001269614	SCV001774147	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29542187, 10777366, 23045425, 15909185, 12707965)
Invitae	RCV001269614	SCV002507760	pathogenic	not provided	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 540 of the FGFR3 protein (p.Asn540Ser). This variant is present in population databases (rs77722678, gnomAD no frequency). This missense change has been observed in individuals with hypochondroplasia (PMID: 10777366, 12707965, 23045425). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16349). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. 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: 11055896, 23165795, 25614871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Suma Genomics	RCV002262566	SCV002543817	pathogenic	Achondroplasia		criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273934	SCV002559067	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002262566	SCV002819863	pathogenic	Achondroplasia	2022-12-28	criteria provided, single submitter	clinical testing	Variant summary: FGFR3 c.1619A>G (p.Asn540Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250598 control chromosomes. c.1619A>G has been reported in the literature in multiple families affected with Hypochondroplasia and shown to segregate with disease (deSanctis_2012, Mortier_2000, Thauvin-Robinet_2003). These data indicate that the variant is very likely to be associated with disease. Other variants at this amino acid, N540K and N540T have also been reported to associate with Hypochondroplasia in the literature. At least one publication reports experimental evidence evaluating an impact on protein function (Patani_2016). These results showed a 10 fold increase in auto-phosphorylation and a 2 fold increase in substrate phosphorylation. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1) and Pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000017758	SCV003841545	pathogenic	Hypochondroplasia	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 0.55). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016349). Different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Lys, p.Asn540Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016337, VCV000016338, VCV000016344, VCV000374828, VCV001325830). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000017758	SCV000038036	pathogenic	Hypochondroplasia	2003-05-15	no assertion criteria provided	literature only