rs77722678
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000142.5(FGFR3):c.1619A>C(p.Asn540Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N540D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000142.5 missense
Scores
Clinical Significance
Conservation
Publications
- achondroplasiaInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Crouzon syndrome-acanthosis nigricans syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
- hypochondroplasiaInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
- lacrimoauriculodentodigital syndrome 2Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- Muenke syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
- thanatophoric dysplasia type 1Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, ClinGen
- thanatophoric dysplasia type 2Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
- camptodactyly-tall stature-scoliosis-hearing loss syndromeInheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
- severe achondroplasia-developmental delay-acanthosis nigricans syndromeInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
- isolated brachycephalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- isolated plagiocephalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LADD syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LADD syndrome 1Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460880Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726800 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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. -
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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) -
Hypochondroplasia Pathogenic:2
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at