Submissions for variant NM_000277.3(PAH):c.329C>T (p.Ser110Leu)

dbSNP: rs199475627

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV002259587	SCV002540148	likely pathogenic	Phenylketonuria	2021-12-16	reviewed by expert panel	curation	The c.329C>T (p.Ser110Leu) variant in PAH has been reported in one individual with mild hyperphenylalanemia, in trans to c.842C>T (p.Pro281Leu) (Likely pathogenic by PAH VCEP variation ID: 589) with exclusion of BH4 deficiency (PMID: 16051511, PMID: 12618080). It has also been observed in an additional patient with hyperphenylalanemia without specified exclusion of BH4 deficiency (PMID: 26542770). In-vitro functional studies are unavailable. This variant is absent from population databases. In-silico predictions yield conflicting results regarding the pathogenicity of this variant. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PP4_moderate, PM2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689609	SCV005185782	uncertain significance	not specified	2024-05-15	criteria provided, single submitter	clinical testing	Variant summary: PAH c.329C>T (p.Ser110Leu) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.329C>T has been reported in the literature in the presumed comopund heterozygous state in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Bayat_2016, Shirzadeh_2018, Hennermann_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26542770, 16051511, 30159852). ClinVar contains an entry for this variant (Variation ID: 102651). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088897	SCV000119495	not provided	not provided		no assertion provided	not provided