chr4-1805644-C-A
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000142.5(FGFR3):c.1620C>A(p.Asn540Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N540T) has been classified as Pathogenic.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 34
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:13
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The FGFR3 c.1620C>A; p.Asn540Lys variant (rs28933068; ClinVarID: 16337) is reported in the literature in multiple individuals affected with hypochondroplasia and achondroplasia (Bellus 1995, Deutz-Terlouw 1998, Xue 2014). Together with another variant resulting in the same amino acid change (c.1620C>G; p.Asn540Lys), these account for over 50% of all hypochondroplasia cases (Bellus 2000, Linnankivi 2012, Xue 2014). The asparagine at codon 540 is highly conserved, and functional analyses of the variant protein show significant reductions in protein expression and kinase activity (Krejci 2008, Raffioni 1998). Based on available information, this variant is considered to be pathogenic. References: Bellus GA et al. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet. 1995 Jul;10(3):357-9. Bellus GA et al. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000 Dec;67(6):1411-21. Deutz-Terlouw PP et al. Asn540Thr substitution in the fibroblast growth factor receptor 3 tyrosine kinase domain causing hypochondroplasia. Hum Mutat. 1998;Suppl 1:S62-5. Krejci P et al. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS One. 2008;3(12):e3961. Linnankivi T et al. Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation. Am J Med Genet A. 2012 Dec;158A(12):3119-25. Raffioni S et al. Effect of transmembrane and kinase domain mutations on fibroblast growth factor receptor 3 chimera signaling in PC12 cells. A model for the control of receptor tyrosine kinase activation. J Biol Chem. 1998 Dec 25;273(52):35250-9. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med. 2014 Nov;2(6):497-503. -
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 540 of the FGFR3 protein (p.Asn540Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with sporadic or familial hypochondroplasia (PMID: 7670477, 8589686, 9452043, 11055896, 23165795, 25614871). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1659C>A. ClinVar contains an entry for this variant (Variation ID: 16337). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate this variant results in significantly reduced expression patterns and reduced STAT1 phosphorylation (Raffioni et al., 1998; Krejci et al., 2008); 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: 22045636, 19088846, 23165795, 19449430, 23614116, 16575888, 9452043, 9857065, 25614871, 10360393, 24630288, 23573386, 24715719, 25505998, 16222682, 16020314, 8589686, 30335613, 30138938, 29620724, 30355600, 31130284, 33942288, 30755392, 32964447, 20301650, 34006472, 33726816, 7670477) -
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Hypochondroplasia Pathogenic:11Other:1
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The observed missense c.1620C>A(p.Asn540Lys) variant n FGFR3 gene has been reported previously in heterozygous state in multiple individuals affected with hypochondroplasia (Xue Y, et al., 2014; Linnankivi T, et al., 2012). This variant has also been reported to segregate with disease in related individuals. Functional studies of the variant protein show significant reductions in protein expression, reduced kinase activity, reduced STAT1 phosphorylation and support a damaging effect on the gene or gene product (Krejci P, et al., 2008; Bellus GA, et al., 2000). The p.Asn540Lys variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Asn540Lys in FGFR3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 540 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
PS2, PS4, PM1, PM2, PM3, PP3 -
Criteria applied: PS4,PM5_STR,PS1,PS3_MOD,PM2_SUP,PP3,PM1_SUP -
PM2_Supporting+PS3_Moderate+PS4+PM6_Strong+PP1_Moderate+PP4 -
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Most common pathogenic variant in hypochondroplasia -
The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 16313190, 23132868). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.73 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039359 /PMID: 1671440 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16227536, 26488179, 9270595, 9531435). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 10588836, 20038778). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderate -
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Achondroplasia Pathogenic:6
Variant summary: FGFR3 c.1620C>A (p.Asn540Lys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 1613230 control chromosomes. c.1620C>A has been reported in the literature in multiple individuals affected with achondroplasia, segregated with disease in at least one family, and was de novo in at least one affected individual (Bellus_1995, Maddirevula_2018). These data indicate that the variant is very likely to be associated with disease. A different variant resulting in the same amino acid consequence has been classified as pathogenic by our lab (c.1620C>G), supporting the pathogenicity of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 7670477, 29620724). ClinVar contains an entry for this variant (Variation ID: 16337). Based on the evidence outlined above, the variant was classified as pathogenic. -
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The c.1620C>A;p.(Asn540Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 16337; PMID: 23573386; 7670477; 8589686; 25614871) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11055896) - PS3_supporting.Same amino acid change as a previously established pathogenic variant regardless of nucleotide change(ClinVar: 16338; PMID 23165795; 25614871) - PS1. This variant is not present in population databases (rs28933068, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 16349; 16344) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
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FGFR3-related chondrodysplasia Pathogenic:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Gain of function is a known mechanism of disease in this gene and are associated with skeletal dysplasias (MIM#146000, #100800, #187600, #187601; PMID: 17320202). Loss of function and dominant negative mechanisms have been proposed to cause autosomal recessive and dominant CATSHL syndrome, respectively (MIM#610474; PMID: 17033969, 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease. Although predominantly associated with dominant disease, at least one family has been described with autosomal recessive CATSHL syndrome (PMID: 24864036). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants typically associated with achondroplasia have also been reported in individuals with hypochondroplasia (PMID: 25614871). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v3; maximum allele count 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Tyrosine Kinase domain (NCBI Conserved domain). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to serine and threonine have been reported in families with hypochondroplasia (PMID: 9452043, 12707965). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. There are multiple submissions in ClinVar classifying this variant as pathogenic and multiple reports of this variant in individuals diagnosed with hypochondroplasia (PMID: 11055896, 16912704). (SP) 0903 - This variant has limited evidence for segregation with disease. One family has been reported where all affected individuals carry this variant (PMID: 7670477). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant results in reduced protein expression and protein function compared to the wild type protein (PMID: 9857065). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Neurodevelopmental delay Pathogenic:1
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FGFR3-related disorder Pathogenic:1
The FGFR3 c.1620C>A variant is predicted to result in the amino acid substitution p.Asn540Lys. This variant is reported to be the most common cause of hypochondroplasia (for example see: Bellus et al. 1995. PubMed ID: 7670477; Linnankivi et al. 2012. PubMed ID: 23165795; Mustafa et al. 2014. PubMed ID: 25505998; Xue et al. 2014. PubMed ID: 25614871; Maddirevula et al. 2018. PubMed ID: 29620724). This variant has been reported in the homozygous state in a patient with severe hypochondroplasia (De Rosa et al. 2014. PubMed ID: 24715719), and has also been reported in patients with thanatophoric dysplasia as part of a complex double de novo FGFR3 allele (Pannier et al. 2009. PubMed ID: 19449430; Marquis-Nicholson et al. 2013. PubMed ID: 23573386). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at