Submissions for variant NM_002016.2(FLG):c.9815_9818del (p.Arg3272fs)

dbSNP: rs769826402

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008323	SCV001168091	pathogenic	not provided	2018-08-22	criteria provided, single submitter	clinical testing	The c.9815_9818delGACA variant in the FLG gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.9815_9818delGACA variant causes a frameshift starting with codon Arginine 3272, changes this amino acid to a Asparagine residue, and creates a premature Stop codon at position 118 of the new reading frame, denoted p.Arg3272AsnfsX118. This variant is predicted to cause loss of normal protein function through protein truncation. The c.9815_9818delGACA variant is observed in 9/30780 (0.03%) alleles from individuals of South Asian background, including one homozygous individual, in large population cohorts (Lek et al., 2016). We interpret c.9815_9818delGACA as a pathogenic variant.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789312	SCV005399523	pathogenic	Ichthyosis vulgaris	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ichthyosis vulgaris (MIM#146700). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic truncating variants tend to result in a more severe condition (PMIDs: 17291859, 30681730). (I) 0112 - The condition associated with this gene has incomplete penetrance. Heterozygous carriers are more likely to be asymptomatic than individuals with biallelic variants (PMIDs: 17291859, 30681730). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a condition (9 heterozygotes, 1 homozygote). (SP) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual (Clinvar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign